Table of Contents - UCSD Continuing Medical Education

X V I I
November 4-8, 2009
World Congress of
PSYCHIATRIC
GENETICS:
Surfing the
Wave of
Discovery
Located at the Manchester Grand Hyatt in San Diego, CA

Table of Contents
PLENARY ABSTRACTS …………………………………………………………………………...3
SYMPOSIA ABSTRACTS ………………………………………………………………………….12
ORAL ABSTRACTS …………………………………………………………………………………..52
POSTER ABSTRACTS
ADHD …………………………………………………………………………………………..100
EARLY CAREER INVESTIGATOR TRACK: ALTERNATIVE
PHENOTYPES, GENE-GENE, AND GENE-ENVIRONMENT INTERACTION …...112
ANIMAL MODELS ………………………………………………………………………...115
ANXIETY DISORDERS ………………………………………………………………..118
AUTISM …………………………………………………………………………………120
EARLY CAREER INVESTIGATOR TRACK: CANDIDATE GENES …………………….124
CANDIDATE GENES ………………………………………………………………………...127
COGNITION …………………………………………………………………………………145
DEMENTIA …………………………………………………………………………………147
ENDOPHENOTYPES ………………………………………………………………………...148
EPIGENETICS …………………………………………………………………………………155
GENE X ENVIRONMENT INTERACTIONS ………………………………………………158
GENETIC COUNSELING ………………………………………………………………..161
GENETIC EPIDEMIOLOGY ………………………………………………………………..162
EARLY CAREER INVESTIGATOR TRACK: GENOMEWIDE AND
META-ANALYTIC APPROACHES ……………………………………………………….168
GENOMICS …………………………………………………………………………………172
HIGH THROUGHOUT SEQUENCING ……………………………………………………….180
MOOD DISORDERS ………………………………………………………………………...180
OTHER CHILDHOOD DISORDERS ……………………………………………………….199
PERSONALITY AND TEMPERAMENT ………………………………………………200
PHARMACOGENETICS ………………………………………………………………..205
SCHIZOPHRENIA ………………………………………………………………………...214
STATISTICS AND BIOINFORMATICS ………………………………………………239
SUBSTANCE ABUSE ………………………………………………………………………...247
LEGEND
P – PLENARY
S – SYMPOSIA
O – ORAL
ECI – EARLY CAREER INVESTIGATOR TRACK
Page

PLENARY
ABSTRACTS

P1.1 NEURONAL PLASTICITY AND
NEURONAL DIVERSITY
F. Gage* (1)
1. The Salk Institute
*gage@salk.edu
The first part of the talk will focus on evidence supporting the
birth and maturation of new neurons in the adult dentate gyrus
of the hippocampus in the mammalian brain. The mechanism
by which the cells integrate and become functional will be
discussed. In addition, the potential functional significance for
adult neurogenesis in the context of the normal function of the
hippocampus will be discussed. In the second part of the talk I
will focus on the recent finding that LINE-1 (Long
Interspersed Nucleotide Elements-1 or L1) retroelements are
active in somatic neuronal progenitor cells (NPCs) providing
an additional mechanism for neuronal diversification.
Together with their mutated relatives, retroelement sequences
constitute 45% of the mammalian genome with L1 elements
alone representing 20%. The fact that L1 can retrotranspose in
a defined window of neuronal differentiation, changing the
genetic information in single neurons in an arbitrary fashion,
allows the brain to develop in distinctly different ways. This
characteristic of variety and flexibility may contribute to the
uniqueness of an individual brain. However, the molecular
mechanism that regulates L1 expression in NPCs is not
completely understood. L1s are likely silenced in neural stem
cells due to Sox2-mediated transcription repression.
Down-regulation of Sox2 accompanies chromatin
modifications, such as DNA de-methylation and
histone acetylation, which in turn may trigger neuronal
differentiation. The characterization of somatic neuronal
diversification will not only be relevant for the understanding
of brain complexity and neuronal organization in mammals,
but may also shed light on the differences in cognitive
abilities.
P1.2 GENETICS OF ALCOHOLISM
G. Schumann* (1)
1. Institute of Psychiatry
*gunter.schumann@kcl.ac.uk
Alcohol use disorders are common psychiatric disorders that
exert a very high cost to the individual and to society. They
are a result of the interplay of multiple behavioural, genetic
and environmental factors. Addictive behaviour is
characterized by phenotypic heterogeneity, epistasis and
polygenicity, implying a contribution of different
neurobiological mechanisms to the clinical diagnosis.
Therefore, treatments for most addiction-related disorders are
often only partially effective, with a substantial proportion of
patients failing to respond. To address heterogeneity and
polygenicity, strategies have been developed to identify more
homogeneous subgroups of patients and to characterize genes
contributing to their (endo-) phenotype. In this presentation,
gene identification strategies using whole genome approaches
as well as translational candidate gene strategies to identify the
genetic and neurobiological basis of addictive behaviour will
be presented, their mechanistic function will be characterised
and their association with endophenotypes relevant for
addiction-related disorders will be described. Applying these
strategies in a translational context aims at improving
therapeutic response by the identification of subgroups of
addiction patients for individualized, targeted treatment
strategies. Finally, a European Integrated Project "IMAGEN",
which investigates reinforcement-related behaviour using
multicentric gene × neuroimaging in 2000 adolescents will be
presented. This project aims to integrate the methodical
approaches discussed above in order to identify the genetic
and neurobiological basis of behavioural traits relevant to the
development of addictions.

P2 DIAGNOSTIC AND PREDICTIVE
GENETIC TESTING IN PSYCHIATRY:
POTENTIAL AND PITFALLS
P2.1 HOW DO PATIENTS RESPOND TO RECEIPT OF
RESULTS FOR A PSYCHIATRIC GENETIC TEST?
P. Mitchell* (1), K. Wilhelm (1), B. Meiser (1), P. Schofield
(2), G. Parker (1)
1. University of New South Wales 2. Prince of Wales Medical
Research Institute
*phil.mitchell@unsw.edu.au
In 2006, we (Wilhelm et al) replicated the gene-environment
interaction between the serotonin transporter gene and
stressful life events in depression which had been reported by
Caspi et al (2003). Although recent meta-analyses have failed
to confirm such an interaction (Risch et al, 2009; Munafo et al,
2009), our study of response of individuals to being informed
of their “depression risk genotype” (Wilhelm et al, 2009), and
that of Green et al (2009) in individuals at risk of Alzheimer
Disease, nonetheless provide the only evidence hitherto of the
response of individuals to an actual (i.e. non-hypothetical)
situation of receiving results from psychiatric genetic
testing. We assessed predictors of the impact of receiving
individual genotype data in 128 participants in a study of
gene-environment interaction in depression onset. Two-thirds
decided to learn their individual genotype results (receivers)
and prior to disclosure this decision was associated with a
perception of greater benefit from receipt of the information.
Receivers completing the 2-week and 3-month follow-up
generally reported feeling pleased with the information and
having had a more positive experience than distress. However,
distress was related to genotype, with those with the “high
risk” s/s allele being most affected. Those who elected not to
learn their results generally did so because of feared
repercussions of being compelled to provide insurance
companies or workplaces with this information. Overall,
there was high interest in, and satisfaction with, learning about
this putative depression risk genotype. The recent report of
Green et al in which children of patients with Alzheimer
disease responded positively to receipt of their APOE
genotype is in accordance with our findings with risk to
depression.
P2.2 COMMUNICATING WITH AFFECTED
INDIVIDUALS AND THEIR FAMILIES
ABOUT PSYCHIATRIC
GENETIC TESTS
J.
Austin* (1)
1.
University of British Columbia
* jehannine.austin@ubc.ca
At present - and at least for the near future - the best method
for predicting an individual’s risk to develop psychiatric
illness is based on documenting a detailed family psychiatric
history, and individualizing empiric recurrence risk data-based
on the unique presenting situation. However, individuals with
psychiatric disorders and their families have expressed interest
in having genetic tests for psychiatric disorders as they
become available. The vast majority of psychiatric genetic
tests will (like the family history based method) yield
probabilistic rather than definitive information about risk to
develop psychiatric illness. Research shows that neither
laypersons nor healthcare providers readily understand
probabilistic genetic risk information. Further, in linking
genetic testing with psychiatric disorders there is the potential
for potentially significant negative consequences, such as
increases in self-stigma, fatalism or risk taking. Facilitating
accurate understanding of psychiatric genetic test results, their
context and implications will be therefore, of paramount
importance. Genetic counseling involves providing families
affected by health conditions that have a genetic component
(like psychiatric disorders) with education and support about
the causes of the illness in the family, genetic testing,
recurrence risks, and management. Although it has
traditionally been thought of as primarily relevant to
pregnancy, or to single gene disorders, the genetic counseling
model is readily applied to individuals with psychiatric
disorders and their families - whether or not they are actively
engaged in family planning. In this presentation, the process of
discussing genetics and psychiatric disorders with affected
families in order to promote perceptions of control over
illness, decrease self-stigma, and facilitate accurate risk
perception
will be detailed from a practical perspective.

P2.3 ATTITUDES TOWARD GENETIC TESTING
AMONG SCHIZOPHRENIA-SPECTRUM
PATIENTS AND
FIRST-DEGREE
RELATIVES
J.
Hoop* (1)
1.
Medical College of Wisconsin
* jhoop@mcw.edu
Rationale: The development of clinically valid psychiatric
genetic tests requires not only empirical data regarding tests’
clinical utility, but also an awareness of and sensitivity to the
likely psychosocial impact on those who are tested. The
current study was designed to explore this issue by gathering
data on the attitudes concerning genetic testing of
schizophrenia-spectrum patients and first-degree relatives.
Methods: In-depth, face-to-face semi-structured interviews
were conducted with 52 outpatients with schizophrenia or
schizoaffective disorder and 50 first-degree relatives of people
with these disorders. Patients also completed the Brief
Symptom Inventory (BSI) measure of psychological distress.
Results: Schizophrenia or schizoaffective disorder patients and
family members expressed strongly positive attitudes toward
pharmacogenetic and susceptibility genetic testing in a range
of clinical scenarios, and expressed more interest in tests with
greater physician involvement, accuracy, and predictive power
(>67%). Patients with higher levels of psychological distress
had significantly more positive attitudes toward testing
(p

P3.1 EPIGENETIC APPROACHES TO
COMMON
DISEASE
A.
Feinberg* (1)
1. Center for Epigenetics, Institute for Basic
Biomedical
Sciences
and Department of Medicine
* afeinberg@jhu.edu
Epigenetics is the study of information, heritable during cell
division, other than the DNA sequence itself, such as DNA
methylation (DNAm), a covalent modification of cytosine.
DNAm is an attractive target for study, because it is easily
measured in archived samples from pre-existing large patient
cohorts. It is now well established from gene-specific studies
that epigenetic alterations are important in cancer, and linked
to oncogene activation, tumor suppressor gene silencing, and
chromosomal instability. We are taking an integrated approach
to catalyze the generalization of gene-specific to genomic
epigenetics, and to advance the focus in this field from cancer
to neuropsychiatric disease. Doing this requires an integration
of new conceptual, technological, epidemiological and
statistical approaches. Population variation in epigenetic
marks may be a predisposing factor for common disease,
consistent with a “common disease genetic and epigenetic”
(CDGE) model. A key element of our approach is the use of
Comprehensive High-throughput Arrays for Relative
Methylation (CHARM), which examines ~4 million CpG sites
throughout the genome without bias toward preconceived
notions of where differential DNAm will be found. We made
the surprising discovery of “CpG island shores,” regions of
intermediate CpG density near high-CpG “islands,” that are a
major target for tissue- and disease-related epigenetic
variation. We have also found population variation in the
stringency of epigenetic marks that may be a predisposing
factor for common disease. This work will likely provide an
important added dimension to genetic studies of common
disease, and may also provide insight into environmental
and
stochastic changes in the genome that
contribute to
neuropsychiatric
disorders.
P3.2
TED REICH YOUNG INVESTIGATOR AWARD
LECTURE
RARE STRUCTURAL VARIANTS IN THE
GENOME AND
COMMON DISORDERS OF
THE
BRAIN
J.
Sebat* (1)
1.
Cold Spring Harbor Laboratory
* sebat@cshl.edu
Studies by our group and others have shown that variation in
genome copy number (CNV) is a major source of genetic
difference among humans and an important contributor to
disease risk. Rare genomic deletions and duplications have
been implicated in multiple neuropsychiatric disorders. In
addition, several mutations have been identified that confer
risk of more than one disorder. Thus, genetic heterogeneity is
a characteristic of all neuropsychiatric disorders; conversely,
phenotypic heterogeneity is a characteristic of all
disease-associated mutations. Identifying and characterizing
rare mutations will be essential to understanding
the
neurobiological
pathways underlying disease.

P4 THE PSYCHIATRIC GWAS
CONSORTIUM
P4.1 CHALLENGES IN WORLD
WIDE GENETIC
ASSOCIATION
STUDIES
S.
Ripke*
* ripke@chgr.mgh.harvard.edu
In this talk, we describe the development and refinement of a
quality control pipeline for genome-wide association SNP
data. This pipeline was developed at MGH in Boston for the
Psychiatric GWAS Consortium Statistical Analysis Group.
The aims of this pipeline are to conduct the quality control of
GWAS-SNP data, impute genotypes based on a reference
sample, and combine the data for mega-analyses. The quality
control steps include the capacity to identify relatives and
overlapping samples in and across studies, as well as to
produce principal components representing population
variation to control for stratification in downstream-analysis
and ancestry outlier exclusion. Through the use of
parallelization and massive computer clusters such as the GCC
(Netherlands), preliminary results can be generated in as little
as
one week, even for study sizes of over 40,000 individuals.
P4.2 PSYCHIATRIC GWAS CONSORTIUM:
MEGA-ANALYSIS OF GWAS FOR MAJOR
DEPRESSIVE DISORDER
P.
Sullivan* (1), Psychiatric GWAS Consortium
1.
UNC/Genetics
* pfsulliv@med.unc.edu
Major depressive disorder (MDD) is a common complex trait
with enormous public health significance. As part of the
Psychiatric GWAS Consortium, the MDD Working Group
conducted a "mega-analysis" of individual level genotype and
phenotype data from 9 genome-wide association studies of
MDD (approximately 12,000 cases and 12,000 controls). All
cases were directly interviewed using a structured diagnostic
instrument and met DSM-IV criteria for MDD. All controls
were population-based and had never met criteria for MDD.
Data files were uploaded to a cluster computer in the
Netherlands and all samples run through a common quality
control, imputation, and analysis pipeline. Careful attention
was paid to investigating and addressing bias (particularly
inflation of type 1 error due to population stratification). An
interim mega-analysis of five samples has been completed,
and the remaining four samples are scheduled for completion
in September 2009. Final results are to be presented
for the
first
time at the WCPG PGC plenary session.

P4.3 COMBINED "FREEZE 1"
SCHIZOPHRENIA-GWAS ANALYSIS
Psychiatric
GWAS Consortium
Due to the very small genetic effects in schizophrenia (SZ)
and the large number of common variants in the human
genome, the detection of susceptibility loci from genome-wide
association studies (GWAS) requires large individual sample
sizes. Moreover, combining datasets with available GWAS
can substantially improve statistical power. Our goal is to
perform a combined analysis of all available SZ GWAS data
sets to detect new associations and to test for confirmation of
previously published ones. To be included in the analysis,
each sample met stringent criteria for quality of phenotypic
data and genotyping. The overall study information and
quality, errors, missing data, population structure, and
intra- and inter-study inflationary factors were assessed.
After
QC exclusions (including sample overlapping and
population outliers), the combined dataset consisted of 10
GWAS studies which included 17 independently collected
clinical samples from Europe, North America, and Australia
with a grand total of >12,200 cases and >9,300 controls
of
European ancestry (Freeze 1). The primary affected
phenotype was defined as either SZ or schizoaffective
disorder. The association analysis is to be implemented
according to a set of a priori decisions following the
QC phase. A set of exploratory phenotypic analyses is also
planned. The Freeze 1 sample includes the large majority of
the SZ case
samples already studied by GWAS of the entire
world.
P4.4 META-ANALYSIS OF GENOME-WIDE
ASSOCIATION STUDIES OF ATTENTION DEFICIT
HYPERACTIVITY DISORDER
B. Neale* (1), Psychiatric GWAS Consortium
1. MGH
*bmneale@gmail.com
We present the first round of meta-analysis for Attention
Deficit/Hyperactivity Disorder (ADHD) as conducted by the
ADHD subgroup of the Psychiatric GWAS Consortium
(PGC). The meta-analysis for ADHD is comprised of six
different core genome-wide association studies: International
ADHD Multisite Genetics (IMAGE) projects I, IMAGE II,
PUMWa, CHOP, McGough, Eli Lilly for a total sample
size of ~2,000 trios and 1,500 cases. These cases have been
matched to shared control resources ensuring protection
against population stratification through identity-by-state
matching. For each of these datasets, we have applied a
standardized quality control pipeline to ensure that the level of
cleaning. These studies have been completed on genome-wide
arrays including Perlegen 600K platform, Affymetrix 5.0,
Illumina 317K, and Illumina 610K, and so we performed
imputation on each of these studies individually to facilitate
the meta-analysis. We combined the test statistics for each of
these studies weighted by the effective sample size (as defined
by power to detect a modest association) and the quality of the
imputation. We present the top findings of this effort as well
as describe the what sort of effects we are unlikely to be
present for ADHD. In addition to the SNP results, we present
the results from interrogating copy number variation across a
subset of these datasets.

P4.5 THE PSYCHIATRIC GWAS CONSORTIUM FOR
BIPOLAR DISORDER: SIGNIFICANT ASSOCIATION
FOR MULTIPLE GENES
J. Kelsoe* (1), The Psychiatric GWAS Consortium
1. University of California, San Diego Dept. of Psychiatry
*jkelsoe@ucsd.edu
Early genomewide association studies of bipolar disorder were
striking for their relative paucity of genomewide significant
genes. This has suggested that common variants that
predispose to bipolar disorder must be of small effect sizes
and that very large samples would be necessary. The PGC-BD
was formed in order to achieve such large sample sizes
through collaboration. Eleven international sites have
combined data from their GWAS studies to produce a
combined sample of 6,806 Caucasian cases and 7,952
controls. Analyses were conducted using PLINK and
BEAGLE. SNPs were imputed to HapMap2, to integrate
across the multiple genotyping platforms. After covarying for
site, population stratification and R2, a genomic control
lambda of 1.12 was obtained. Four regions achieved nominal
genomewide significance (p

P4.7 CROSS-DISORDER WORKGROUP: TAKING
DNA BEYOND DSM
J. Smoller* (1), Cross Disorder Group
1. Massachusetts General Hospital
*jsmoller@hms.harvard.edu
Over the past 25 years, genetic epidemiologic studies have
provided compelling evidence for shared genetic influences on
a range of psychiatric disorders. In addition, the common
comorbidity of different diagnoses supports the hypothesis of
substantial overlap in the underlying biology of
clinically-defined syndromes. The vast scope of the PGC
provides unprecedented power to examine and dissect the
shared heritability underlying psychiatric disorders using
genomewide data. The PGC’s Cross Disorder Group (CDG)
was established to pursue this aim by coordinating and
conducting meta-analyses to identify convincing
genotype-phenotype associations that overlap or transcend
traditional diagnostic phenotypes. In this presentation, we
will discuss the scientific rationale for cross-disorder analyses,
insights from genetic studies in other areas of medicine, and
proposed analytic approaches. Cross-disorder analyses may
answer fundamental questions about the genetic basis
of
psychopathology and provide a crucial resource for
developing an etiology-based nosology for psychiatry.

SYMPOSIA
ABSTRACTS

S1 ANTIDEPRESSANT
PHARMACOGENETICS: GWAS AND
BEYOND
S1.1 COMPARATIVE PHARMACOGENOMICS OF
SEROTONERGIC AND NORADRENERGIC
ANTIDEPRESSANTS: A GENOME-WIDE ANALYSIS
OF THE GENDEP SAMPLE
R. Uher* (1), N. Perroud (1), M. Ng (1), M. Rietschel (2), W.
Maier (3), O. Mors (4), J. Hauser (5), N. Henigsberg (6), B.
Jerman (7), D. Souery (8), A. Placentino (9), P. Muglia (10),
A. Butler (1), S. Cohen-Woods (1), K. Aitchison (1), A.
Farmer (1), I. Craig (1), C. Lewis (1), P. McGuffin (1)
1. King’s College London 2. Central Institute of Mental
Health, Mannheim 3. University of Bonn 4. Aarhus University
Hospital 5. Poznan University of Medical Sciences 6.
University of Zagreb 7. Jozef Stefan Institute, Ljubljana 8.
Université Libre de Bruxelles and Psy Pluriel 9. Centro San
Giovanni di Dio, FBF, Brescia 10. GlaxoSmithKline
*rudolf.uher@kcl.ac.uk
The substantial individual variability in response to
antidepressants appears to be partially genetically determined,
but functional candidate genes have little predictive power.
We report a genome-wide association study with a continuous
trait of antidepressant response, indexed as percentage
improvement on a depression severity scale over 12 weeks of
treatment with either a serotonin-reuptake-blocking
antidepressant escitalopram or a predominantly
norepinephrine-reuptake-blocking antidepressant nortriptyline.
High quality Illumina Human 610-quad chip genotyping was
available for 706 unrelated participants of European ancestry
treated with escitalopram (n=394) or nortriptyline (n=312) in
the Genome-based Therapeutic Drugs for Depression
(GENDEP) project. Two regions containing common copy
number polymorphisms were associated with outcome of
treatment with either antidepressant at suggestive levels of
significance (p=3.8x10-7 and p=7.4x10-7). A marker in a
neurogenesis-related gene was associated with response to
nortriptyline at a genome-wide level of significance
(p=3.6x10-8) and a predicted functional marker in a gene
involved in immune response was the best predictor of
response to escitalopram (p=2.8x10-6). While limited
statistical power means that a number of true associations may
have been missed, these results suggest that efficacy of
antidepressants may be predicted by genetic markers other
than traditional candidates. If replicated, these findings may be
among the first steps on a genome-wide avenue towards
personalized medicine for depression.
S1.2 A GENOME-WIDE ASSOCIATION STUDY OF
CITALOPRAM RESPONSE IN THE STAR*D SAMPLE
S. Hamilton* (1), H. Garriock (1), J. Kraft (1), S. Shyn (1), E.
Peters (1), J. Yokoyama (1), G. Jenkins (2), M. Reinalda (2),
Slager (2), P. McGrath
1. UCSF 2. Mayo Clinic
*steve.hamilton@ucsf.edu
Antidepressant response is likely influenced by genetic
constitution, but the actual genes involved have yet to be
determined. We have carried out a genome-wide association
study to determine if common DNA variation influences
antidepressant response. Our sample is derived from Level 1
participants in the Sequenced Treatment Alternatives to
Relieve Depression (STAR*D) study, all treated with
citalopram. Association for the response phenotype included
883 responders and 608 non- responders. For the remission
phenotype, 743 subjects that achieved remission were
compared to 608 non-responders. We used a subset of 430K
SNPs from the Affymetrix 500K and 5.0 Human SNP Arrays,
and association analysis was carried out after correcting for
population stratification. We identified three SNPs associated
with response with p-values less than 1 x 10-5 near the
UBE3C gene, another 100kb away from BMP7, and a third
that is intronic in the RORA gene. These same SNPs were
also associated with remission. Thirty-nine additional SNPs
are of interest with p-values ≤ 0.0001 for the response and
remission phenotypes. Although the findings reported here do
not meet a genome-wide threshold for significance, the
regions identified from this study provide targets for
independent replication and novel pathways to investigate
mechanisms of antidepressant response. This study was not
placebo controlled, making it possible that we are also
observing associations to non-specific aspects of drug
treatment of depression.

S1.3 FIVE YEAR FOLLOW-UP IN THE KAISER
PERMANENTE GENES AND RESPONSE TO
ANTIDEPRESSANTS (GRAD) STUDY
C. Schaefer* (1), L. Shen (1), V. Reus (2), C. Quesenberry
(1)
1. Kaiser Permanente Division of Research 2. Department of
Psychiatry University of California San Francisco
*cathy.schaefer@kp.org
The GRAD study is a prospective cohort study of genetic and
non-genetic factors associated with response to antidepressant
treatment in an ethnically diverse cohort of 1,004 adults with
major depression. Standard assessments of therapeutic
response and side effects were completed at initiation, 4
weeks, and 8 weeks after participants began pharmacotherapy
with fluoxetine or paroxetine. After 8 weeks, 70% had
responded with a 50% reduction in Hamilton Depression Scale
scores. Approximately five years following the acute
treatment phase of the study, 764 (76%) participants were
re-interviewed and electronic medical records were abstracted
to determine long term response to antidepressant treatment,
including residual symptoms, episode recurrence, treatment
resistance, and response to alternative medications. The
follow-up study included the same proportion of responders
(70%) and nonresponders (30%) as the acute treatment phase.
Analyses of factors associated with therapeutic response after
8 weeks, as well as with outcomes of treatment after five
years, have been conducted for nongenetic factors and for
variants in candidate genes related to current
pharmacodynamic and pharmacokinetic hypotheses
concerning response to SSRI antidepressants. A genome-wide
association study is planned. This longitudinal investigation
of the cohort’s subsequent syptomatology, episode recurrence,
treatment adherence, and response to alternative drugs will
serve to define a new set of phenotypic variables that more
accurately reflect disease heterogeneity and may better relate
to underlying genetic variation than variables derived from
observations made during acute treatment alone.
S1.4 A GENOMEWIDE ASSOCIATION STUDY
POINTS TO MULTIPLE LOCI THAT PREDICT
ANTIDEPRESSANT DRUG TREATMENT OUTCOME
IN DEPRESSION
S. Lucae* (1), M. Ising (1), E. Binder (1), T. Bettecken (1),
M. Uhr (1), S. Ripke (1), M. Kohli (1), J. Hennings (1), S.
Horstmann (1), S. Kloiber (1), A. Menke (1), B. Bondy (2), R.
Rupprecht (2), K. Domschke (3), A. Rush (4), F. Holsboer (1),
B. Mueller-Myhsok (1)
1. Max Planck Institute of Psychiatry, Munich, Germany
2. Department of Psychiatry, Ludwig Maximilians University,
Munich, Germany 3. Department of Psychiatry, Westfalian
Wilhelms University, Muenster, Germany 4. Department of
Psychiatry, University of Texas, Southwestern Medical
Center, Dallas, USA
*lucae@mpipsykl.mpg.de
The efficacy of antidepressant drug treatment is
unsatisfactory; 1 in 3 patients does not fully recover even after
several treatment trials. It was the aim of this study to identify
genetic and clinical determinants of antidepressant drug
treatment. We performed a genomewide pharmacogenetic
association study in 339 depressed inpatients from the Munich
Antidepressant Response Signature (MARS) project and in
361 pooled DNAs from an independent German replication
study. A set of 328 SNPs highly related to outcome in both
studies was genotyped in 832 samples of the STAR*D study.
We generated a multilocus genetic variable that described the
individual number of alleles of the selected SNPs with
beneficial treatment outcome in the MARS sample
(“response” alleles) to evaluate additive genetic effects on
antidepressant drug treatment outcome. Multilocus analysis
revealed a significant contribution of a binary variable that
categorized patients as carriers of a high vs. low number of
response alleles in the prediction of antidepressant treatment
outcome in both samples (MARS and STAR*D). In addition,
we observed that patients with a comorbid anxiety disorder
combined with a low number of response alleles showed the
least favourable outcome. These results demonstrate the
importance of multiple genetic factors combined with clinical
features in the prediction of antidepressant drug treatment
outcome, which underscores the multifactorial nature of this
trait.

S1.5 TOWARDS POPULATION-BASED
ANTIDEPRESSANT PHARMACOGENOMICS
R. Perlis* (1)
1. Massachusetts General Hospital
*rperlis@partners.org
Recent genome-wide association studies in psychiatric
disorders strongly suggest that very large cohorts will be
required to detect the many common variants of modest
effects which are likely to underlie psychiatric phenotypes.
Individual large clinical trials may be insufficient to detect or
replicate such variants, much less determine their clinical
validity. An alternative approach makes use of large electronic
medical records databases to identify subjects with the
phenotypes of interest and obtain blood for DNA collection
from them. Strategies to validate the outcomes of interest in
these data sets and address sources of heterogeneity have been
developed, allowing a novel cohort of 3,000 subjects treated
for MDD to be collected. Such population-based approaches
offer a feasible, low-cost means of identifying genetic and
clinical predictors of treatment response for psychiatric
disorders.
S2 DNA METHYLATION IN HUMAN BRAIN
AND NEUROPSYCHIATRIC DISEASES
S2.1 COMPREHENSIVE DNA METHYLATION
ANALYSIS IN NEURONS AND NON-NEURONS FROM
HUMAN POSTMORTEM BRAINS AND ITS
APPLICATION TO MENTAL DISORDERS
T. Kato* (1), K. Iwamoto (1)
1. RIKEN Brain Science Institute
*kato@brain.riken.jp
The role of DNA methylation in the pathophysiology of
mental disorders has not been well established yet, in spite of
recent studies using a candidate gene approach or a
comprehensive DNA methylation analysis in the brain. The
brain is a heterogeneous tissue, and there may be substantial
differences of DNA methylation status between cell types.
Thus, we should clarify the DNA methylation difference
between neurons and glial cells to search for the genes
differentially methylated in the neurons of patients with
mental disorders. For this purpose, we are analyzing the DNA
methylation differences between neuronal and non-neuronal
nuclei. After separating neuronal nuclei from frozen human
brains using anti-NeuN antibody and fluorescent cell sorter,
we performed comprehensive DNA methylation analysis
using promoter tiling arrays and site-specific methylation
analysis of about 1500 CpG sites using Illumina Golden Gate
assays. Global methylation level was also assessed by a
LUMA assay. Neuronal nuclei tended to be hypomethylated
compared with non-neuronal nuclei, and methylation patterns
of bulk brain tissue were more similar to the patterns in
non-neuronal nuclei compared with neuronal nuclei. Genes
commonly methylated both in neuronal and non-neuronal
nuclei included genes related to cell-cycle. Neuronal- and
non-neuronal nuclei showed distinctive DNA methylation
patterns, compatible with their functional differences.
Application of this method to patients with mental disorders
will provide a clue to understand the role of epigenetics in
mental disorders.

S2.2 DNA METHYLATION SIGNATURES WITHIN
THE MAJOR DEPRESSIVE DISORDER BRAIN
S. Sabunciyan (1), M. Aryee (1), R. Irizarry (1), M. Webster
(4), R. Yolken (1), A. Feinberg (1), J. Potash* (1)
1. Johns Hopkins School of Medicine 2. Uniformed Services
University
*jpotash@jhmi.edu
Major depressive disorder (MDD) is influenced by genetic
factors, but heritability has been estimated at 37%.
Genome-wide association studies are ongoing to identify
sequence variation that influences MDD susceptibility.
Epigenetic marks, such as DNA methylation, which can be
influenced by the environment, may also play a role in MDD
etiopathogenesis. Here we present a genome-wide DNA
methylation scan in MDD. We compared 39 postmortem
MDD brain samples and 27 control brain samples, all
prefrontal cortex, obtained from the Stanley Medical Research
Institute. DNA from these samples was hybridized to our
Comprehensive High-throughput Arrays for Relative
Methylation (CHARM) platform. This 2.1 million probe
platform assays 140,000 genomic GC-rich regions with an
average of 15 probes per region. Smoothing is performed
across each region to derive a single methylation value per
region. Follow-up is being done using bisulfite
pyrosequencing to validate results. Gene expression levels will
be assayed by real-time RT-PCR for correlation with
methylation patterns.
S2.3 QTLS FOR GENE-SPECIFIC METHYLATION IN
HUMAN BRAIN
D. Zhang* (1), L. Cheng (1), J. Badner (1), C. Chen (1), D.
Craig (2), M. Redman (2), E. Gershon (1), C. Liu (1)
1. The University of Chicago 2. The Translational Genomic
Research Institute
*dandanz@uchicago.edu
We have observed extensive inter-individual differences in
DNA methylation at specific CpG sites in human adult
cerebellum. To study genetic factors that might affect this
variation we studied CpG sites of 14,495 genes, almost all
from promoter regions. We performed a genome-wide single
nucleotide polymorphism (SNP)-based association mapping
for methylation Quantitative Trait Loci (mQTLs) in 153 adult
cerebellum samples. Cis-association refers to methylation
correlation with SNPs within 1 megabase of a CpG site. 1,923
SNP-CpG pairs showed cis-association that was region-wide
significant by permutation. Of these SNP-CpG pairs, 629 were
also phenotype-wide significant (after additional permutation
corrections for all the tested methylation phenotypes).
Methylation level was negatively correlated with gene
expression in the cerebellum for 14 of 15 genes with
significant cis-association (FDR q value

S2.4 REGULATION AND FUNCTION OF CPG
METHYLATION AND DNA METHYLTRANSFERASES
IN POST-MITOTIC NEURONS
R. Sharma* (1)
1. University of Illinois at Chicago
*rsharma@psych.uic.edu
We know the domain structure, substrate preference,
protein-protein interactions, and cellular expression profiles
(including brain) of the major DNA methyltransferases. We
also now know that DNA methyltransferases are demonstrably
albeit variably expressed in the adult brain, and that global
CpG methylation of brain DNA is abundant, dynamic,
modular and possibly disease related. We also know that in
individual gene studies, promoter CpG methylation can be
modified in response to neuronal depolarization, behavioral
and cognitive experimentation, and pharmacological
treatments. And yet, remarkably little is known about the
regulation/function of either CpG methylation or DNA
methyltransferases in the post-mitotic neurons as in the
developing or adult brain. We have approached this question
by attempting to identify the cis-regulatory sequences
upstream of the transcription start site (TSS) in postmitotic
primary neuron cultures as a best approximation to their
in-vivo regulation in brain neurons. In these studies, we are
able to demonstrate a vigorous promoter activity with DNA
protein interactions in the immediate region surrounding the
TSS. Parallel studies have included a DNMT1 knockdown
strategy in neurons, where we can demonstrate a role for DNA
methytransferases in the regulation of candidate gene
promoter methylation. Also, neuronal depolarization as a
model of neuronal activity causes a decrease in DNMT1 and
DNMT3a mRNA expression. The accumulating evidence
suggests that the function and regulation of CpG methylation
and DNA methyltransferases in neurons is partly unique to
these post-mitotic cells.
S2.5 CORRELATIONS BETWEEN GENE
EXPRESSION AND DNA METHYLATION IN HUMAN
BRAIN
C. Chen* (1), D. Zhang (1), L. Cheng (1), J. Badner (1), E.
Gershon (1, 2), C. Liu (1)
1. Department of Psychiatry, The University of Chicago,
Chicago, IL 60637 2. Department of Human Genetics, The
University of Chicago, Chicago, IL 60637
*chenchaor@gmail.com
DNA methylation plays a critical role in the regulation of gene
expression. Here, we studied the correlation of DNA
methylation and gene expression at the genome level in the
human brain. The methylation status of 27,578 CpG sites from
14,495 genes in 153 cerebellum samples was measured in our
lab using Illumina HumanMethylation27 BeadChips.
Cerebellum gene expression data for 45 of these individuals
were obtained from the Stanley Medical Research Institute
Online Genomics Database, having been analyzed with
Affymetrix Genechip Human Genome U95 Set. After
eliminating covariate and batch effects, and excluding low
quality data, we identified the CpG sites that were within 10kb
of the transcription start site (TSS) of a gene measured on the
expression array. Five hundred fifty-three CpG sites were
located within 10 kb of one or more TSSs, resulting in 625
CpG site-expression pairs for correlation analysis.
Seventy-five nominally significant correlations were observed.
Twenty-four of them remained significant after multiple test
correction (FDR, q ≤ 0.05). Twenty of the 24 (83.3%)
significant correlations were negative, as expected.
Interestingly, at four CpG sites (16.7%), increased DNA
methylation was associated with increased gene expression.
We did not observe a significant correlation between gene
expression and DNA methylation for imprinted genes.

S3 RISK VARIANTS THROUGH BIOLOGY
TO TREATMENT: MAPPING THE
CHALLENGES AND THE POTENTIAL
S3.1 DELINEATING THE EFFECT ON SZ OF GWAS
IDENTIFIED RISK ALLELES BASED ON
NEUROPSYCHOLOGICAL PERFORMANCE.
G. Donohoe* (1), J. Walters (2), D. Morris (1), L. Kaladjieva
(3), A. Jablensky (3), M. Gill (1), M. O'Donovan (1), D.
Rujescu (4), M. Owen (2), A. Corvin (1)
1. Trinity College Dublin 2. Cardiff University 3. University
of Western Australia 4. Munich University
*donoghug@tcd.ie
Recent SZ genome wide association studies have led to the
identification of several new risk loci for the disorder. The
biological role of these variants is largely unknown, making
an understanding of the neural mechanisms they control a
priority. One approach to this question is the cognitive
intermediate or endophenotype approach. This was originally
proposed as a method of gene discovery but increasingly is
used as a means of identifying the neural mechanisms by
which risk is conferred. The endophenotype strategy in
psychiatric genetics is based on a number of critical (and
criticised) assumptions, including the unproven assumption
that it is located on the risk pathway between illness
phenotype and genotype, thus acting to either mediate or
modify risk. If this is unlikely for all risk variants, then
distinguishing between those variants whose risk is
cognitively mediated from variants that are not will be
informative about the neural mechanism underlying this risk.
Demonstrating its utility, we will present data on the
application of this approach to first allele to have received
genome wide support for psychosis: The Zinc Finger Protein
804A gene (ZNF804A), which is brain-expressed but of
unknown function. We tested for association between
ZNF804A rs1344706 and cognitive functions known to be
impaired in schizophrenia (IQ, episodic memory, working
memory, and attentional control) in an Irish discovery sample.
We then tested significant results in a German replication
sample. We observed an interaction between ZNF804A
genotype and diagnosis for measures of episodic and working
memory in the Irish patient sample but not controls. These
findings replicated in the same direction in the German
sample. Furthermore, in both samples the association between
ZNF804A and schizophrenia strengthened when patients with
lower general cognitive function were excluded. We conclude
from these data that in a disorder characterized by
heterogeneity, a risk variant at ZNF804A appears to delineate
a patient subgroup characterized by relatively spared cognitive
ability. Further work is required to establish if this represents a
discrete molecular pathogenesis that differs from other patient
groups and whether this also has consequences for nosology,
illness course or treatment.
S3.2 THE EFFECTS OF RISK VARIANTS ON BRAIN
STRUCTURE, FUNCTION AND CONNECTIVITY
A. Macintosh
S3.3 MUTANT MOUSE MODELS:
PSYCHOPATHOLOGY AND TRANSLATIONAL
PSYCHOPHARMACOLOGY
J. Waddington* (1), C. O'Tuathaigh (1)
1. Royal College of Surgeons in Ireland
*jwadding@rcsi.ie
In the face of the complexity of psychiatric disorders, the
etiology of which likely involves a combination of genetic and
environmental factors, a number of key technologies are
converging: for example, identification of putative
susceptibility genes through GWAS and CNV studies leads to
investigation of the behavioural roles of these genes by
targeted manipulation in mice and their phenotypic
characterisation (‘gene-driven’ approach); in a complementary
manner, identification of putative pathophysiological
processes and indicative therapeutic pathways leads to
investigation of behavioural phenotype in mice mutant for
genes regulating such processes and pathways
(‘phenotype-driven’ approach). There are many challenges in
mutant phenotyping as it relates to models of
psychopathology, underlying brain mechanisms and
psychopharmacological profiling, and in translating findings
in mutants to the identification of novel therapeutic targets.
Recent studies relating to psychosis particularly illustrate these
issues. Gene x environment and gene x gene interactions
constitute additional problems. Despite rapid advances over
the past several years, it is clear that we continue to face
substantive challenges in applying mutant models to better
understand the genetics of psychopathology. However, the
breadth and depth of ongoing studies holds the prospect
of progress. The authors' studies are supported by Science
Foundation Ireland and the Health Research Board.

S3.4 SCHIZOPHRENIA PATHOGENESIS: INSIGHTS
FROM ETIOLOGICALLY VALID MOUSE MODELS
OF RARE DISEASE VARIANTS
J. Gogos* (1)
1. Columbia University
*jag90@columbia.edu
Genetic variation influences the risk for and manifestation of
mental illnesses. In light of recent genetic advances,
psychiatric genetics is currently at a crossroads concerning
how to efficiently translate genetic findings into meaningful
insights for disease prevention and treatment. Teasing apart
the contribution of genetic variants to neural development and
function, and ultimately disease risk, necessitates the use of
model systems. In order for mutant animal models to uncover
a genuine pathogenetic link between a candidate gene and
disease risk, the association of the genetic variant must be
unequivocal, its functional effect known and the risk allele
modeled accurately. Studies assessing rare variants have
identified specific, causative and highly penetrant
schizophrenia-associated alleles. These rare alleles are far
more likely to have deleterious functional consequences than
common alleles due to clear effects on gene products. As a
result they can be faithfully modeled in mice and have higher
potential for revealing genuine insights into disease
pathogenesis. In this talk we review results from the study of
mouse models of rare schizophrenia-associated structural
variants generated and characterized in our lab. We found that
rare disease-associated variants result in specific impairments
in cognition and brain connectivity and identified some of the
molecular and cellular/synaptic processes underlying these
impairments. The latter can serve as substrates for novel drug
development efforts.
S3.5 ESTABLISHMENT OF A METHOD FOR
HIGH-THROUGHPUT FUNCTIONAL SCREENING OF
PATIENT REGULATORY & CODING VARIANTS IN
MICE
J. Schmouth (1, 2), R. Bonaguro (1), C. de Leeuw (1, 3), L.
Dreolini (4), R. Holt (4, 5, 6), E. Simpson* (1, 3, 5)
1. Centre for Molecular Medicine and Therapeutics at the
Child & Family Research Institute, University of British
Columbia, Vancouver, Canada 2. Genetics Graduate Program,
University of British Columbia, Vancouver, Canada 3.
Department of Medical Genetics, University of British
Columbia, Vancouver, Canada 4. Canada's Michael Smith
Genome Sciences Centre, British Columbia Cancer Agency,
Vancouver, Canada 5. Department of Psychiatry, University
of British Columbia, Vancouver, Canada 6. Department of
Molecular Biology and Biochemistry, Simon Fraser
University, Burnaby, Canada
*simpson@cmmt.ubc.ca
Large scale association studies and deep sequencing are
generating huge numbers of human variants for which the
functional significance is unknown. Traditionally, the mouse
is the in vivo model in which to assay candidate human
mutations. However, standard mouse approaches do not
effectively address the challenges of this dataset: many of the
mutations may be regulatory, not coding; variant-phenotypic
effect may be small; and most variants will not be mutations.
We propose an approach that addresses these issues. A human
BAC, >100 kb including the gene of interest and variant
region, is “recombineered” to carry the candidate variant. The
BAC is also retrofitted for homologous recombination at a
locus 5' of the Hprt1 gene in ESCs, and mice derived. Since
each variant will be studied without copy number or site of
insertion variation, direct functional comparisons can be made.
Because the human allele is not located at the homologous
mouse locus, the variant can be tested in the presence of two,
one, or no mouse alleles. The latter, in which brain
development and function are entirely dependent upon the
human allele, may best reveal subtle Wt versus variant
differences. Currently in testing are variants of NR2E1; a gene
critical for neural stem cell function and “associated” with
bipolar disorder. Germline animals carrying the Wt human
allele have been obtained and variants are in chimeras and
ESCs. Thus, we will test the functional significance of human
NR2E1 variants and provide “proof in principle” for this
approach to test other gene variants.

S3.6 PROMOTION OF SYNAPTIC AND CIRCUIT
MATURATION PARTIALLY REVERSES SYMPTOMS
IN A MOUSE MODEL OF RETT SYNDROME
D. Tropea* (1, 2), E. Giacometti (3), N. Wilson (2), R.
Iaenisch (3), M. Sur (2)
1. Trinity College Dublin 2. MIT 3. Whitehead Institute
*tropea@mit.edu
Rett Syndrome (RTT) is a neurodevelopmental disorder
caused by mutations in the gene coding for methyl
CpG-binding protein 2 (MECP2). We examined the
hypothesis that MeCP2 deficiency leads to a deficit in the
maturation of synapses and circuits in the cerebral cortex of
MeCP2 null mice. Consistent with the hypothesis, we found
reductions in synaptic amplitudes measured by patch clamp
recording from motor cortex neurons, reductions in the
postsynaptic density protein PSD95 in motor cortex measured
with immunohistochemistry, and reductions in the density of
spines on motor cortex neurons. An in vivo assay of synapse
maturation and developmental plasticity in visual cortex
revealed that synapses had abnormally prolonged plasticity in
MeCP2 null mice. Microarray analyses have shown that the
Insulin-like Growth Factor 1 (IGF-1) signaling pathway has a
key role in the stabilization and maturation of cortical
synapses. Thus, we reasoned that upregulation of the IGF-1
pathway would reverse symptoms in MeCP2 null mice.
Systemic treatment of young MeCP2 mutant mice with an
active fragment of IGF-1 increased synaptic amplitudes,
upregulated cortical PSD95 and stabilized cortical plasticity to
wild-type levels. In addition, the treatment extended the life
span of the mutant mice, partially restored regularity in heart
rate and breathing, and improved locomotor function. Our
results suggest that truncated or full-length IGF-1 are
promising candidates for pharmacological treatment of Rett
Syndrome, and potentially of other CNS disorders caused by
delayed synaptic maturation. A similar approach can be used
for studying the molecular mechanisms and potential therapies
of other neurodevelopmental disorders, such as Autism
Spectrum Disorders (ASD) and schizophrenia.
S4 GENOME-WIDE ASSOCIATION STUDIES
ON MAJOR DEPRESSION: WHAT’S NEXT?
S4.1 GENOME-WIDE ASSOCIATION STUDIES IN
MAJOR DEPRESSION. THE ROLE OF
ENDOPHENOTYPES
W. Hoogendijk* (1), P. Sullivan (2), Z. Bochdanovits (3), M.
Bevova (3), S. Woudstra (4), B. Penninx (4), P. Heutink (3)
1. Dept. Psychiatry, VU University Medical Center 2.
Department of Genetics, Psychiatry, & Epidemiology, UNC
Chapel Hill, Department of Genetics, USA 3. Section Medical
Genomics, Department of Clinical Genetics, VU Medical
Center, Amsterdam, the Netherlands 4. Department of
Psychiatry, Neuroscience Campus VU medical center
Amsterdam, the Netherlands
*w.hoogendijk@ggzingeest.nl
According to the WHO, depression will be the second leading
cause of disability worldwide by 2020. Diagnostic accuracy
and prediction of treatment-outcome is limited by subjective
phenotypic assessments and would strongly benefit from
biological endophenotypes, together with
genome-wide genotyping. Gene-expression of peripheral
blood cells, measured as RNA concentrations, is the
endophenotype that is most proximal to the genotype. The
endophenotype that is most proximal to the brain disorder
is brain structure and function, assessed
using (functional) magnetic resonance imaging (fMRI).
Recent data from our campus in twins concordant or
discordant for depression and anxiety have indicated that
abnormal responses to emotional stimuli are associated
primarily with genetic factors, whereas hippocampal atrophy
was observed only in discordant twins and is therefore likely
to be due to environmental factors. Several studies have tried
to associate individual candidate genes with neuroimaging
data as endophenotype. However, results are inconclusive,
especially concerning depression. Recently, a genome wide
association study (GWAS) for MDD was performed on
subjects from Netherlands study on depression and anxiety
(NESDA) and the Netherlands twin register (N= 1738 cases
and 1802 controls). Eleven SNPs within the top 200 smallest
p-values appeared to be within to the presynaptic piccolo
(PCLO) gene (Sullivan et al., Mol. Psychiatry 2009). Here, we
report on preliminary results on the association of these PCLO
SNPs with endophenotypes like brain morphology and
activity in depressed subjects compared to healthy controls.

S4.2 GENOME-WIDE ANALYSIS IN MAJOR
DEPRESSION - AND NOW?
B. Müller-Myhsok* (1)
1. MPI Psychiatry, Munich
*bmm@mpipsykl.mpg.de
Major Depression is a common disorder with a heritable
component clearly established. However, conventional
association studies, including GWAs, have shown
comparatively little success. This apparent lack of success
may be related to an overly simplistic underlying model. Thus
a refined model or additional data might be necessary. These
additional aspects include gene by gene, gene by environment
interaction, rare variants, especially CNVs and animal models.
In the second part of my talk I will focus on gene by
environment interaction.
S4.3 MICE THEN HUMANS: A COMPLEMENTARY
APPROACH TO DISSECTING THE BIOLOGY OF
MDD
P. Sullivan* (1)
1. UNC/Genetics
*pfsulliv@med.unc.edu
It is possible that the etiological underpinnings of major
depressive disorder (MDD) are more intricate than for other
complex traits. The phenotype may blend into normalcy,
etiological heterogeneity could be marked, genetic effects may
be very subtle, and gene-environment interactions may be
particularly salient. If true, then sample size requirements in
humans for unbiased, genome-wide studied are prohibitively
large. In this talk, I will describe an alternative approach. With
Drs Lisa Tarantino, Fernando Pardo-Manuel de Villena and
UNC colleagues, we have recently received a NHGRI center
of excellence award to attempt to dissect MDD-like behaviors
in mouse. This work is made possible due to the development
of a new systems biology platform, the Collaborative Cross,
along with advances in mouse genomics (e,g. a new
Affymetrix mouse GWAS array) and dense phenotyping.
Central to our study is an experimental manipulation to assess
the impact of stressful environments and gene-environment
interactions on MDD-like behaviors. The fundamental idea is
to screen the vast number of possible genetic and
gene-environment effects to derive a far smaller number of
models. High probability models can then be tested in human
samples. This approach will yield a detailed understanding of
MDD-like mouse behavior, and the applicability of these
models can then be tested in humans.
S4.4 GENOME-WIDE PREDICTION OF FUNCTIONAL
GENE-GENE INTERACTIONS FOR DEPRESSION
Z. Bochdanovits* (1)
1. VU Medical Center
*z.bochdanovits@vumc.nl
The contribution of individual risk factors to complex
disorders is modest and current strategies aimed at identifying
such susceptibility genes in very large case-control studies are
still thought to be underpowered. One biologically obvious
reason why susceptibility genes would be difficult to identify
based on searching for their main effects alone is that in reality
they might work together in a non-additive fashion, i.e. the
risk is actually conveyed by specific combinations of such
factors. Although this possibility is widely acknowledged, a
full screen for epistatic effects on a genome-wide scale is
unfeasible because statistical power would be seriously
compromised by correcting for multiple testing. One possible
way to avoid this problem is to ascertain pairs of variants that
a priori are more likely to be involved in functional gene-gene
interactions and test only these for association with a complex
phenotype. Classical population genetic theory predicts that
linkage disequilibrium (LD) between interacting loci will
emerge if the phenotype affected by the combination of loci is
under selection. Consequently, ascertainment of gene-pairs
based on deviation from two-locus equilibrium genotype
frequency could predict functional interactions. We applied
this approach to multiple genome-wide datasets and propose
gene-pairs that are potentially involved in conveying
susceptibility to depression.

S4.5 DISCOVERY AND TESTING OF DELETIONS
FOR ASSOCIATION WITH MDD IN GAIN STUDY
M. Bevova*(1), Z. Bochdanovits (1), E. de Geus (2), G.
Willemsen (2), B. Penninx (2), D. Boomsma
(2), W. Hoogendijk (2), P. Heutink (1)
1. VUMC 2. VU
*m.bevova@vumc.nl
GWAS on major depressive disorder (MDD) had been
performed in the frame of six initial Genetic Information
Network studies. This study was conducted in GAIN-MDD
cohort comprised of 1738 MDD cases and 1802 controls
genotyped for around 435 000 SNPs using a Perlegen array.
There are different methods of discovering CNVs in
genome-wide data sets. Most methods based on intensity
differences between SNP alleles allowing detection of CNV
gains and losses. A chemistry of the Perlegen platform
however, do not allow to distinguish intensity differences and
therefore CNV gains, but we still have the opportunity to
identify CNV losses (deletions). Several approaches based on
violation of Hardy–Weinberg or Mendelian transmission as
well as on non random distribution of null genotypes enable to
identify deletions from genotype data only. We developed an
algorithm there we first used 30 trios from GAIN-MDD cohort
to discover deletions using MICRODEL software and then we
use runs of homozygosity and stretches of missing genotypes
in the GAIN MDD unrelated cohort as a footprint for possible
deletions in genotyping data as defined by adjusted settings of
PLINK software. Detected runs of homozygosity and missing
genotypes for each individual will be compared with the CNV
dataset obtained from trio data. Individuals having either runs
of homozygosity or missing genotypes overlapping with
deletion identified by MICRODEL software in trios are
considered as having a deletion in this region. For the
identified deletions with frequencies >1% association studies
with MDD as a main outcome has been performed.
S5 NEW INSIGHTS FROM STUDIES OF
RARE STRUCTURAL VARIATION IN
PSYCHIATRIC DISORDERS
S5.1 SCHIZOPHRENIA: A COMMON DISEASE DUE
TO MULTIPLE RARE ALLELES?
M. King (1), J. McClellan (1)
1. University of Washington
Objectives: To review the role of rare structural variants in
persons with schizophrenia. Methods: We screened
genome-wide for genomic deletions and duplications in 150
individuals with schizophrenia and 268 ancestry-matched
healthy controls, using array CGH technology. We focused on
rare mutations of size >100kb that disrupted genes, that were
only detected in cases or in controls, and that were not
reported in the Database of Genomic Variants (DGV). Results:
Individuals with schizophrenia were significantly more likely
to harbor rare deletions and duplications mutations than
healthy controls (15% vs 5%, P = 0.0008). This risk was even
higher in patients with onset of illness by age 18 years of age
(20% vs 5%, P = 0.0001). Each affected individual harbored a
different mutation that impacted different genes. Mutations in
cases disproportionally disrupted genes involved in
neurodevelopment, including neuregulin and glutamate
pathways (Walsh et al., Science 2008). Independent groups
have since confirmed and extended these findings (Xu et al.,
2008; Stefansson et al., 2008; International Schizophrenia
Consortium, 2008; Need et al., 2009). Our present work
extends these experiments to rare small structural variants and
to rare point mutations. Conclusions: Individuals with
schizophrenia are more likely than healthy persons to harbor
rare structural events that delete, duplicate, or disrupt genes.
These results suggest that a substantial portion of
schizophrenia arises from rare mutations, either de novo or
very recent in origin. This degree of genetic heterogeneity has
important implications for genetic and treatment research.

S5.2 DELETIONS IN NRXN1 IN SCHIZOPHRENIA
G. Kirov* (1), D. Rujescu (2), A. Ingason (3), D. Collier (4),
M. O'Donovan (1), M. Owen (1)
1. MRC Centre for Neuropsychiatric Genetics and Genomics,
School of Medicine, Cardiff University, Heath Park, Cardiff,
CF14 4XN, United Kingdom 2. Division of Molecular and
Clinical Neurobiology, Dept. of Psychiatry, University of
Munich, Germany 3. Research Institute of Biological
Psychiatry, Mental Health Center Sct. Hans, Copenhagen
University Hospital, Roskilde, Denmark 4. Social, Genetic and
Developmental Psychiatry Centre, Institute of Psychiatry,
King's College, London, UK
*kirov@cardiff.ac.uk
Several studies have implicated deletions in NRXN1 in the
aetiology of schizophrenia. Similar findings are also available
in the literature on autism. We have conducted a joint analysis
on all available studies on CNVs in schizophrenia, in order to
assess the significance of these reports. At the time of writing
there are 7 studies that have published data on
non-overlapping samples. The total number of subjects studied
have been 7,935 patients with schizophrenia, and 41,234
controls. We re-analysed all available data for CNVs >100kb,
in order to make all studies comparable. We find 15 deletions
in cases (0.19%) and 17 in controls (0.04%). This corresponds
to a Fisher Exact Test p=0.000047; OR 4,59; 95% CI
2,29-9.17. The results are very similar for those CNVs that
disrupt exons (12 in cases and 9 in controls). We conclude that
the association for NRXN1 deletions in schizophrenia is
strongly supported by the evidence. However, more samples
should be analysed, and higher-resolution platforms should be
used in future studies, in order to confirm the findings and
identify which deletions are pathogenic.
S5.3 VERY RARE CNVS ASSOCIATED WITH
BIPOLAR DISORDER
D. Zhang (1), C. Liu (1), E. Gershon* (1)
1. University of Chicago
*egershon@yoda.bsd.uchicago.edu
With the paucity of significant associations from GWAS
analyses of Schizophrenia and Bipolar disorder, the
underlying common-variant association model has been called
into question. Rare variants such as Copy Number Variations
(CNVs) could account for some of the missing variance
(difference between heritability in twin studies and variance
accounted for by GWAS). Comparative intensity of
hybridization (or similar) signal at each locus studied with
GWAS chips can be used to detect CNVs. The size of CNVs
that are reliably detectable is limited because of the average 3
kb distance between markers. There are batch effects and
other artifacts of microarray data, and the software used for
analyzing intensity data (CEL files in the Affymetrix system)
and calling CNVs varies in accuracy. Bipolar disorder: GWAS
data was analyzed to detect CNVs in 1001 cases and 1034
controls from the Bipolar Genome Study (BiGS), using the
Affymetrix single nucleotide polymorphism (SNP) 6.0
platform. Plate-wise normalization was done by the
Affymetrix Power Tool plug-in to Birdsuite 1.5.2. Very rare
CNVs (singletons; occur once in a data set) were significantly
more frequent in Bipolar patients than in controls (Zhang et
al., 2009). Quantitative PCR (qPCR) was used to validate
CNVs. These data are consistent with numerous rare variants
contributing to a very heterogeneous disorder. Multiple
software packages exist for analyzing CEL files and for
calling CNVs. These include Birdsuite, HelixTree (Golden
Helix, Inc.), Partek, and PennCNV-Affymetrix. For singleton
deletions, confirmation by qPCR was most consistent for
Birdsuite and Partek, and least consistent for HelixTree.

S5.4 FROM CNV “HOT SPOTS” TO THE REST OF
THE GENOME, LOOKING BEYOND THE LOW
LYING FRUIT
S. Jonathan* (1)
1. Cold Spring Harbor Laboratory
*sebat@cshl.edu
Recent studies have established an important role for rare
structural variants in the etiology of schizophrenia and other
psychiatric disorders. Studies of rare variants have so far been
limited to relatively large (>100 kb) copy number variants
(CNVs). However, large CNVs account for a very small
fraction of all variants and presumably account for only a
subset of risk alleles. In order to further enhance the power of
the CNV-based approach, new computational and
experimental strategies must be considered. Promising new
computational approaches to the analysis of CNVs include
gene-based and pathway-based association methods. We will
present preliminary findings from these studies, and we will
address the specific technical challenges that apply to CNV
data. New experimental methods that are in development for
highly-sensitive detection of CNVs include new microarray
CGH and Next Generation sequencing platforms. We will
address how these methods can be applied to genetic studies
of psychiatric disease.
S5.5 ANALYSIS OF RARE STRUCTURAL VARIANTS
IN BIPOLAR DISORDER AND SCHIZOPHRENIA
S. Purcell* (1)
1. Mass General
*shaun@pngu.mgh.harvard.edu
We and others have previously reported evidence that
implicates rare, large deletions and duplications as strong risk
factors for schizophrenia, both at specific loci and in terms of
genome-wide burdens. In this talk, I consider a number of
related questions: 1) the role of structural variants in bipolar
disorder, 2) an analysis of the intersection of regions emerging
from association analysis of common single nucleotide
polymorphism data with rare structural variant data, and 3)
methodological issues in testing for enrichment of variants in
affected individuals occurring in particular sets of genes.
S6 PSYCHIATRIC DISORDER
BIOMARKERS
S6.1 THE QUEST FOR PSYCHIATRIC DISORDER
BIOMARKERS: FROM DIFFERENTIAL EXPRESSION
TO ISOFORMS TO PATHWAYS
C. Turck* (1), R. Landgraf (1), M. Filiou (1), Y. Zhang (1),
C. Webhofer (1), G. Maccarrone (1), C. Ditzen (1)
1. Max Planck Institute of Psychiatry
*turck@mpipsykl.mpg.de
Proteomic technologies in combination with pathway analysis
promise to be of great value in molecular medicine,
particularly in the discovery and validation of disease markers.
The research of the “Proteomics and Biomarkers” group is
aimed at the identification of markers that can categorize
subsets of psychiatric patients in a more consistent manner
than is presently achievable. This will allow a more precise
definition and categorization of affective disorders and in turn
facilitate investigations of the pathogenesis of the diseases and
enhance the ability for treatment. Biomarker detection efforts
range from classical proteomics approaches such as
quantitative mass spectrometry of brain tissue and body fluid
proteins to phage display screens with cerebrospinal fluid
antibodies. A particular focus is the use of animal models that
represent selected endophenotypes characteristic for the
respective clinical phenotype in humans. A comprehensive
and sensitive proteomics platform that is based on metabolic
labeling of mouse models with stable isotopes is used for mass
spectrometry quantitation and disease relevant pathway
discovery. In a complementary approach human specimens
from patient groups that have been characterized according to
their clinical as well as endophenotypes are analyzed. An
antibody array platform serves to interrogate a great number of
proteins in human cerebrospinal fluids with the aim to extract
patterns of biomarkers that can be used for clinical diagnosis.

S6.2 BIOMARKER DISCOVERY IN SCHIZOPHRENIA
AND BIPOLAR DISORDER: TRANSCRIPTOMIC,
SPLICEOMIC, AND PATHWAY ANALYSIS FINDINGS
S. Glatt (1), C. Bousman (2), G. Chana (2), S. Chandler (2),
W. Kremen (2), I. Everall (2)
1. Department of Psychiatry and Behavioral Sciences, and
Medical Genetics Research Center; SUNY Upstate Medical
University; 750 East Adams Street; Syracuse, NY, 13210;
U.S.A. 2. Center for Behavioral Genomics; Department of
Psychiatry; University of California, San Diego; 9500 Gilman
Drive; La Jolla, CA 92039; U.S.A.
Recently, high-throughput biomarker discovery efforts have
focused on profiling various “omes” to assist in elucidating
dynamic molecular signatures in major psychiatric disorders.
For the last four years, our group has focused largely on the
transcriptome (i.e., the full compendium of mRNAs expressed
in a given tissue) as a potential source of biomarkers for
various mental disorders. Gene expression levels are
heritable, yet are also influenced strongly by environmental
and epigenomic influences; thus, the transcriptome may
represent a final common pathway wherein the joint
influences of genome, epigenome, and envirome may be
represented. This ability to represent multiple influences may
be an advantage for a biomarker discovery platform when
considering complex multifactorial polygenic disorders, such
as psychiatric disorders. In this presentation, we will provide
a review of our recent efforts utilizing these approaches to
identify viable biomarkers for schizophrenia (SCZ) and
bipolar disorder (BPD). These efforts have included the use of
supervised and unsupervised hierarchical clustering of
individual transcripts; receiver-operating curve analyses;
ANOVA and ANCOVA; ontology, pathway, and protein
structure-similarity analyses; and home-grown biostatistical
and bioinformatic approaches. The various strengths and
weaknesses of these approaches will be discussed in the
context of our empirical work that has implicated various
genes and biological pathways as sources of potentially useful
biomarkers for SCZ, BPD, and their sometimes-shared feature
of psychosis. We will conclude with a discussion of how
these findings may be interrelated and how they may guide
future biomarker discovery efforts.
S6.3 IDENTIFICATION OF BLOOD BIOMARKERS
FOR PSYCHOSIS USING CONVERGENT
FUNCTIONAL GENOMICS
S. Kurian (1), H. Le-Niculescu (2), S. Patel (2), D. Bertram
(3), C. Dike (4), N. Yehyawi (3), J. Davis (3), P. Lysaker (3),
M. Caligiuri (5), J. Lohr (4, 5), D. Lahiri (2), J. Nurnberger
(2), S. Faraone (6), M. Geyer (5), M. Tsuang (5), N. Schork
(1), D. Salomon (1), A. Niculescu* (2, 3)
1. Scripps Research Institute 2. Indiana University 3.
Indianapolis VA Medical Center 4. San Diego VA Medical
Center 5. UCSD 6. SUNY Upstate
* anicules@iupui.edu
There are to date no objective clinical laboratory blood tests
for psychotic disease states. We provide proof of principle for
a Convergent Functional Genomics (CFG) approach to help
identify and prioritize blood biomarkers for two key psychotic
symptoms, one sensory (hallucinations) and one cognitive
(delusions). We used gene expression profiling in whole blood
samples from patients with schizophrenia and related
disorders, with phenotypic information collected at the time of
blood draw, then cross-matched the data with other human and
animal model lines of evidence. Topping our list of candidate
blood biomarkers for hallucinations, we have four genes
decreased in expression in high hallucinations states (Fn1,
Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high
hallucinations states (Arhgef9, Phlda1,S100a6). All of these
genes have prior evidence of differential expression in
schizophrenia patients. At the top of our list of candidate
blood biomarkers for delusions, we have fifteen genes
decreased in expression in high delusions states (such as Drd2,
Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and sixteen genes
increased in high delusions states (such as Nrg1, Egr1, Pvalb,
Dctn1, Nmt1, Tob2). Twenty five of these genes have prior
evidence of differential expression in schizophrenia patients.
Predictive scores, based on panels of top candidate
biomarkers, show good sensitivity and negative predictive
value for detecting high psychosis states in the original cohort
as well as in three additional cohorts. These results have
implications for the development of objective laboratory tests
to measure illness severity and response to treatment in
devastating disorders such as schizophrenia.

S6.4 LITHIUM MEDIATED EXPRESSION CHANGES
IN LYMPHOBLASTOID CELL LINES
H. Chen (1), M. Burmeister (1), M. McInnis* (1)
1. University of Michigan
* mmcinnis@umich.edu
Lithium (Li) is an effective maintenance therapy of bipolar
disorder (BPD). There are several hypotheses on the
mechanism of lithium’s action, many derived from studies that
have utilized post-mortem brain tissue from bipolar
individuals. The changes of gene expression in postmortem
tissue exposed to Li are confounded by agonal and other
factors such as postmortem interval, tissue pH, medication
status, age, and sex. Lymphoblastoid cell lines (LCL) derived
from subjects with the illness of interest represent an
accessible proxy cellular system to study gene expression
patterns. We studied gene expression in 12 LCLs cultured
with and without presence of 1 mM LiCl in the culture for 4,
8, and 16 day using the Illumina RefSeq8_v2 BeadChip
microarrays. We identified 218 transcripts that showed
significant changes over the time course of Li treatment at
false discovery rate (FDR) < 5%. Of the 218 significant
transcripts, only C8orf33 showed a consistently positive slope
change in expression pattern, and the rest showed negative
slope changes in expression. C8orf33 is a novel gene mapped
to the region of 8q24 linked to BPD. Molecular interaction
analysis using the Michigan Molecular Interaction data base
(MiMI) search algorithms identified that C8orf33 directly
interacted with three other genes (GIT1, GPRASP1, and
HAP1), and through indirect interactions forms a network of
total 144 nodes (genes) and 345 edges. Among the 144 nodes,
21% of them were reported to be regulated by Li in mouse
brain (McQuillin et al., 2007). Functional annotation analysis
using the EASE algorithms suggests that the 144 genes in the
network are enriched in biological pathways, including a
G-protein coupled receptor protein signaling pathway
(p=2.27E-8), neuroactive ligand-receptor interaction(P =
7.38E-16), calcium signaling pathway (P = 7.90E-10), and
regulation of actin cytoskeleton (P = 3.16E-05). Our data
suggest that individual gene expression changes induced by Li
treatment are modest. The results reported here suggest a
model that includes the effect from networked genes
contributes to the molecular basis of Li's therapeutic action.
S6.5 EXON ARRAY FINDINGS IN LYMPHOBLASTIC
CELL LINES IN SCHIZOPHRENIA
M. Vawter
S7 SMALL RNA IN NEUROPSYCHIATRY
S7.1 BIOINFORMATIC ANALYSIS OF POTENTIAL
MIRNA INVOLVEMENT IN PSYCHIATRIC DISEASE
S. Jugurnauth*, G. Breen, D. Collier
*sarah.jugurnauth@kcl.ac.uk
The ability of microRNAs to regulate expression of genes via
UTR regions opens up these relatively overlooked sequences
as new candidates for disease susceptibility. In many cases
associations map to "gene deserts", and association peaks
often indicate areas where no causative change is obvious. A
number of these fall within computationally predicted miRNA
target sites as reviewed in Barnes 2007. MiRNAs, with their
increasingly recognized roles in neurodevelopment and
synaptic plasticity may contribute to the multiple genetic
factors influencing the as yet unknown dysfunction and/or
neurodevelopmental incidents believed to result in psychiatric
disease. Evidence is emerging for aberrant miRNA expression
or miRNA involvement in many psychiatric diseases including
schizophrenia, autism spectrum disorder, alzheimers disease,
neurodegenerative disorders and behavioral disorders. I intend
to support evidence for disruptive SNPs in candidate miRNA
target sites to highlight miRNAs that might impact on
neurotransmission pathways and pathways involving
candidate psychiatric genes. Identification of relevant
computationally predicted target sites will take the following
into account, multiple targets in a gene, strength and quality of
targets, target prediction by more than one software, gene
weighting and function, similar expression levels and location
of miRNA and target previously observed in literature,
previous associations with neuropsychiatric disease in
candidate region, target accessibility (mRNA folding) and
where possible epistasis and eQTL pQTL data.

S7.2 ALTERATION OF CORTICAL MICRORNA
BIOGENESIS IN SCHIZOPHRENIA AND ITS
INFLUENCE ON GENE EXPRESSION
M. Cairns (1), N. Beveridge (1), A. Carroll (1), E. Gardiner
(1), P. Tooney (1), D. Santarelli (1)
1. Schizophrenia Research Institute, Sydney. School of
Biomedical Sciences, The University of Newcastle. Hunter
Medical Research Institute
* murray.cairns@newcastle.edu.au
Gene expression is altered in multiple brain regions in
schizophrenia. While some of these changes relate directly to
changes at the DNA level, most are probably a function of
regulatory influences. Bioinformatic approaches are helping to
make sense of these changes by identifying pathways and
networks of related genes with plausible implications for this
complex phenotype. Unfortunately, this analysis is yet to
provide a cohesive and reproducible signature indicative of
systematic failure in gene regulation. In our laboratory, we
have been investigating the hypothesis that
post-transcriptional gene silencing is altered in schizophrenia,
causing an underlying change in the regulatory matrix. In
support of this we have identified widespread alteration of
microRNA expression in two cortical regions that appeared to
be a consequence of elevated miRNA biogenesis. This
corresponded with an increase in the expression of DGCR8, a
component of the microprocessor complex involved in
post-transcriptional modification and regulation of most
primary microRNA transcripts. Interestingly, this
up-regulation of miRNA expression is inversely correlated
with gene expression in these tissues and could have important
implications for the development and progress of
schizophrenia - perhaps through the regulation of genes
involved in synaptic structure and function, which feature
strongly amongst predicted target genes.
S7.3 ALTERATION OF THE GENE REGULATORY
NETWORK IN THE FRONTAL CORTEX OF
HIV-INFECTED INDIVIDUALS
E. Tatro* (1), I. Everall (1)
1. UCSD School of Medicine Department of Psychiatry
* etatro@ucsd.edu
Background: MicroRNAs are small, non-coding RNAs that
regulate gene networks, helping control cell function and
phenotype. MicroRNAs are recognized as key players in CNS
patterning, function, and disease. Past studies focused on
expression levels of coding mRNAs in the brain of
HIV-infected individuals. Because microRNAs affect the
abundance and downstream functions of mRNAs, it is
important to understand both mRNA and miRNA changes
concurrently. We report the first genome-wide microRNA
profile in the HIV-infected human frontal cortex. We present
methods to integrate mRNA expression with microRNA
expression data in a Target BiasAnalysis by determining the
probability that the number of target-genes of dysregulated
miRNAs would be dysregulated in HIV infection versus
expected by chance. Methods: We used Affymetrix arrays for
comparing gene expression in frontal cortex from
6HIV-infected males (no cognitive impairment or
encephalitis) and 6 age-matched controls at the mRNA level.
We pooled equivalent RNA samples and utilized Applied
Biosystems PCR-based array to assess a panel of 379
microRNAs. Results: Target bias analysis indicated that
microRNAs clustered into four types: A) Those with many
dysregulated mRNA targets of less stringent significance, B)
Fewer dysregulated target-genes of highly stringent
significance, C) spectrum from non-bias to combinations of A
and B. The dysregulated miRNAs clustered on Chromosomes
14, 17, 19, and X. Those miRNAs that affect many genes may
be important "circuits" in gene regulatory networks pertinent
to the effects of HIV infection in CNS. These may be
functional and diagnostic markers of neurologic disease in
HIV-infected patients.

S7.4 MICRORNAS IN THE TRANSITION FROM
CONTROLLED TO COMPULSIVE COCAINE-TAKING
P. Kenny (1), J. Hollander (1), H. Im (1)
1. The Scripps Research Institute
* pjkenny@scripps.edu
Rats with extended access to cocaine over prolonged time
periods can develop compulsive-like cocaine seeking
behaviors, including intake that progressively escalates. The
dorsal striatumis considered an important brain region in the
development of compulsive cocaine intake. MicroRNAs are
small (21–23 nucleotides) noncoding RNA transcripts that
regulate many basic aspects of cell biology, but little is known
of their roles in addiction. We investigated the role for
microRNAs in the dorsal striatum in regulating the
development of escalated cocaine intake in rats with extended
access to the drug. We found that microRNA-212 (miR-212)
was significantly up regulated in the dorsal striatum of rats
with extended (6-h) daily access to cocaine
self-administration, demonstrating compulsive-like escalated
intake, compared with rats that had restricted (1-h) access and
cocaine-naïve rats. Furthermore, miR-212overexpression in
dorsal striatum decreased, whereas its inhibition increased,
cocaine intake only in rats with extended but not restricted
access to thedrug. Finally, we found that the effects of
miR-212 on cocaine-taking were regulated in part through the
novel CREB coactivator TORC. These findings identify
miR-212 as a cocaine-responsive microRNA whose
expression is increased in dorsal striatum in rats that
over-consume cocaine. Moreover, miR-212 may be a novel
protect factor against the development of compulsive
cocaine-taking behaviors. Finally, we identify apreviously
unknown role TORC in regulating drug-taking behavior.
Noncoding RNAs such as the microRNAs may thus serve as a
novel targets for the future development of anti-addiction
therapeutics.
S8 ATTENTION DEFICIT HYPERACTIVITY
DISORDER: ENVIRONMENTAL
INFLUENCES ON THE GENOME
2009 RICHARD TODD AWARD LECTURE
S8.1 WHOLE GENOME METHYLATION STUDY OF
48 MONOZYTGOTIC PAIRS CONCORDANT OR
DISCORDANT FOR ATTENTION PROBLEMS
R. Althoff* (1), D. Boomsma (2), C. van Beijesterveldt (2), P.
Rizzu (2), E. de Geus (2), F. Middleton (3), Y. Zhang-James
(3), S. Faraone (3), J. Hudziak (1)
1. University of Vermont 2. VU University 3. SUNY Upstate
University
* ralthoff@uvm.edu
Despite large sample sizes Genome Wide Association Studies
for ADHD have produced relative few new genetic
associations. We sought to determine if a whole genome
methylation scan of monozygotic twin pairs, who mostly share
their DNA sequence, would reveal new genetic areas for
study. Method: 48 monozygotic (MZ) twin pairs from the
Netherlands Twin Registry were selected for persistent
longitudinal concordance or discordance on CBCL attention
problems (AP). Extracted buccal DNA from 11 discordant
pairs, 20 concordant affected, and 17 concordant unaffected
was restriction digested and incubated with antibodies to
5-methylcytosine. Antibody-bound DNA was separated from
non-antibody bound DNA and the antibodies were removed to
reveal methylation sites on the DNA. After PCR amplification
methylated DNA was hybridized for Affymetrix Human
Promoter Arrays tiled upstream and downstream of every
known gene. Raw signal values for each of the 400 probes for
each promoter were extracted, quantile normalized, and
median polished within each promoter region. The end result
was median methylation signals for each of 16,441 gene
promoter regions. Empirical distributions for each twin type
were created as a screening tool to identify those promoter
regions where concordant affected, concordant unaffected and
discordant twin pairs differ more from each other than from
other individuals in the sample. MZ co-twin methylation
falling outside of this empirical distribution interval for a
particular individual was considered a possible positive result.
Results revealed significant differences between discordant
twins in at least one gene region previously associated with
attention problems in animal models.

S8.2 THE DEVELOPMENTAL COURSE OF GENE
EXPRESSION IN BRAINS OF RATS PRENATALLY
EXPOSED TO POLYCHLORINATED BIPHENYLS
T. DasBanerjee* (1), F. Middleton (1), S. Faraone (1)
1. SUNY Upstate Medical University
* dast@upstate.edu
Although ADHD is a heritable neurobehavioral disorder,
environmental influences or gene-environment interactions
play an important role. Studies in humans and animals support
the relationship between exposure to polychlorinated
biphenyls (PCBs) and risk of developing ADHD. In this study,
we investigated the developmental course of expression of
ADHD candidate genes, or IMAGE genes, in Sprague-Dawley
(SD) rats exposed to PCBs prenatally and postnatally. We
performed gene expression analysis of three brain regions (the
prefrontal cortex, midbrain and vermis), which abundantly
express the IMAGE genes. We analyzed three time points-
PND23, PND35 and PND70. At each time point we have 36
rats (18 males, 18 females; within each gender, 6 controls, 6
exposed to PCBs only gestationally and 6 exposed to PCBs
only during lactation).The brains were harvested at the above
time points and used for isolation of RNA from each brain
region. For microarray screen, we pooled equal amounts of
RNA from each animal in each group and each brain area to
create a total of 36 RNA samples for analysis (18 samples in
duplicate). RNA was processed using the recommended
Affymetrix protocol and hybridized to the GeneChip Rat Gene
1.0 ST array. Our results show that a small subset of IMAGE
genes shows robust differences in expression in some or all
brain regions of PCB-exposed SD rats compared to SD
controls. A couple of these genes (COMT, Csnk1a1) have
been confirmed by real time quantitative PCR (p< 0.005).
Collectively, the data provide strong evidence that exposure to
PCBs, either gestational or lactational, can lead to profound
effects on the brain circuits involved in ADHD.
S8.3 A PILOT STUDY OF METHYLATION IN ADHD
YOUTH PRENATALLY EXPOSED TO CIGARETTE
SMOKE
S. Faraone* (1), F. Middleton (1), T. DasBanerjee (1), Y.
Zhang-James (1), Tourette GWAS Consortium
1. SUNY Upstate Medical University
* faraones@upstate.edu
Attention deficit hyperactivity disorder (ADHD) is a complex
disorder having both genetic and environmental causes. Both
human and animal model studies show that prenatal exposure
to cigarette smoke is a risk factor for ADHD symptoms and
associated features. Despite this evidence, little is known
about the mechanisms whereby smoke exposure increases risk
for ADHD. We hypothesized that methylation of ADHD
candidate genes by cigarette exposure could be one such
mechanism. As a preliminary test of this hypothesis, we
examined the methylation status of 51 ADHD candidate genes
in 34 subjects from the International Multisite ADHD
Genetics (IMAGE) project, using DNA extracted from blood:
15 ADHD smoke exposed subjects, 4 non-ADHD smoke
exposed siblings; 10 ADHD non-smoke exposed subjects and
5 non-ADHD non-smoke exposed siblings. We assessed
methylation using bisulfite treatment followed by analysis on
the Human Promoter 1.0R Array (Affymetrix). Signal data
from all annotated CpG islands in the genome were extracted
and quantile normalized. Then, the probe and CpG island data
for individual IMAGE candidate genes were compared
between subject groups. After correction for multiple
comparisons, we found no significant effect of either ADHD
status or smoke exposure on methylation values. However,
three genes showed nominally significant (p

S8.4 JOINT EFFECTS OF TOXIN EXPOSURES AND
RISK GENOTYPES ON ADHD SYMPTOMS
J. Nigg* (1)
1. Oregon Health & Science University
* niggj@ohsu.edu
Two studies are presented here that illustrate both
psychosocial environment and biological environment effects
on gene correlation with ADHD in children. In study 1, blood
lead is examined in 347 children carefully characterized with
regard to ADHD or non-ADHD status. Blood lead is reliably
associated with ADHD symptoms. However, when iron
metabolism (HFE) and dopamine genes are considered, a
composite genotype is created that is invulnerable to the lead
effect (r=.00), versus a risk genotype that exhibits robust
response to blood lead (r=.30, p

S9.2 USING NEUROCOGNITION AS AN
ENDOPHENOTYPE IN A GWAS DATASET
K. Burdick* (1), P. DeRosse (1), T. Lencz (1), A. Malhotra
(1)
1. The Zucker Hillside Hospital; Feinstein Institute for
Medical Research; Albert Einstein College of Medicine
* kburdick@lij.edu
One promising strategy proposed as a way to simplify the
genetics of complex disorders, such as schizophrenia, has been
through the use of intermediate phenotypes or
endophenotypes. An endophenotype is a measurable trait that
is thought to be more closely linked to the underlying
pathophysiology of the disease than is the categorical
diagnosis itself. The use of such biomarkers in molecular
genetic studies may enhance power to detect susceptibility loci
first by reducing the complexity of the phenotype through
dissecting it into its component parts and second by assaying a
trait that is believed to be more proximal to gene action. A
growing body of evidence suggests that measures of
neurocognitive function may have utility in genetic studies by
enhancing power and/or elucidating gene function at the
endophenotype level. However, while the originally proposed
methodology was to first identify genetic variants associated
with the endophenotype and then subsequently to test for their
effects on risk for illness, most studies to date have used these
traits as post-hoc to disease susceptibility analyses. In the
current study, we attempted to utilize the endophenotype
approach as it was initially intended. Specifically, we
conducted a genome-wide association study (GWAS) in 200
Caucasian healthy controls using general cognitive ability (g)
as the primary outcome measure. We then tested the top five
hits for case-control association in 249 healthy controls and
280 patients with schizophrenia. This presentation will focus
on the findings from these analyses, including the detection of
novel schizophrenia-associated loci.
S9.3 PHARMACOGENETIC APPROACHES IN A
GENOME-WIDE DATASET
A. Malhotra* (1), T. Lencz (1), J. Zhang (1), J. Kane (1), D.
Robinson (1)
1. The Zucker Hillside Hospital; Feinstein Medical Research
Institute; Albert Einstein College of Medicine
* malhotra@lij.edu
Genome-wide association studies (GWAS) are now being
utilized across a number of phenotypes in psychiatric research,
including studies that seek to identify molecular genetic
factors influencing antipsychotic drug response. To date, these
studies have been limited by phenotypic heterogeneity
(including multiple drugs, dosages, and levels of compliance)
and smaller sample sizes than usually recommended for
GWAS; more innovative study designs may need to be
considered. We have embarked on a large scale study that
aims to combine the strengths of GWAS with the advantages
of focused candidate gene work to identify variants than
influence antipsychotic drug efficacy and adverse events
associated with treatment. Initially, we will conduct a GWAS
in a group of patients characterized by clinical assignment to
treatment with clozapine, the atypical antipsychotic drug
commonly reserved for treatment refractory patients, and
compare the clozapine-treated patients to
non-clozapine-treated patients as a proxy measure of treatment
responsiveness. Top SNPs will be functionally characterized
with in vivo and in vitro approaches; functionally relevant
SNPs will then be assessed in large prospectively treated
cohort of 1000 first episode schizophrenia patients collected in
the U.S and Europe for relationship to drug efficacy and
drug-induced weight gain. In this presentation, we will present
early data with this approach including: GWAS data
identifying SNPs within 5 genes that were differentially
distributed between groups (p< 5 x 10-6); candidate gene work
implicating specific promoter region polymorphisms in first
episode schizophrenia patients’ clinical response to treatment
as well as propensity for acute weight gain and finally; data
from a recent meta analysis suggesting that the dopamine D2
receptor (DRD2) gene plays a modest, yet significant, role in
the variation in antipsychotic drug efficacy.

S9.4 ALTERNATIVE PHENOTYPES IN BIPOLAR
DISORDER: DOES UNDERLYING GENETIC
ARCHITECTURE MAP ONTO CLINICAL
FEATURES?
J. Kelsoe, T. Greenwood, K. Oedergaard, R. McKinney,
Bipolar Genome Study (BiGS)
It has long been suspected that different aspects of bipolar
disorder might have different genetic bases and study of a
specific subform might reduce the problem of genetic
heterogeneity. Large scale GWAS studies have now given us
both the genotyping density and sample sizes to begin to
address this question. In support of the idea are studies that
demonstrate the familiality of a variety of clinical
presentations such as psychotic mania, irritable mania,
comorbid anxiety disorders or substance abuse and many
others. Our collaborative group has taken great pains to assess
these clinical features and have been actively examining their
value as alternative phenotypes. In general, it seems clear that
many alternative phenotypes provide stronger evidence of
association than seen in the analysis of the entire sample
despite much smaller samples sizes. Striking examples of this
are irritable mania, comorbid migraine and disability. Though
in an early stage these analyses suggest different genetic bases
to these different forms. This elucidation of underlying
architecture may guide biological hypotheses of disease.
S10 OBSESSIVE COMPULSIVE DISORDER
AND TOURETTE DISORDER: PHENOTYPE,
GENOTYPE AND GENOME-WIDE
ASSOCIATION STUDIES
S10.1 OBSESSIVE COMPULSIVE DISORDER AND
TOURETTE DISORDER: PHENOTYPE, GENOTYPE
AND GENOME-WIDE ASSOCIATION STUDIES.
C. Mathews (1), D. Cath (2), P. Arnold (3), J. Scharf (4), S.
Stewart (4), D. Pauls * (4)
1. Department of Psychiatry, University of California Medical
School, San Francisco, CA; USA 2. Department of Psychiatry,
University of Utrecht, the Netherlands 3. Hospital for Sick
Children, University of Toronto, Toronto, Ontario, Canada 4.
Psychiatric and Neurodevelopmental Genetics Unit, Center for
Human Genetic Research, Massachusetts General Hospital,
Harvard Medical School, Boston, MA, USA
* dpauls@pngu.mgh.harvard.edu
Obsessive Compulsive Disorder (OCD) and Tourette Disorder
(TD) are familial, phenotypically heterogeneous
neuropsychiatric disorders that are likely to have a shared
genetic etiology with additional independent genetic and
non-genetic contributors. The first two presenters will discuss
attempts to disaggregate these conditions into more
homogeneous quantitative phenotypes. In the first
presentation, factor and latent class analyses of 1,200 and
1,600 individuals with OCD, respectively, will be described.
Results suggest an underlying latent OCD susceptibility and
five symptom-based factors (contamination, taboo, doubts,
hoarding/perfectionism, superstitions/rituals), four of which
are heritable. In the second presentation, latent class analyses
of 500 TD-affected individuals will be summarized. Three
classes of tics (socially inappropriate behaviors/tics, head tics,
body tics) were observed, one of which (body tics) is
heritable. The next speaker will summarize a family-based
association study of 308 OCD families in which DLGAP3 (the
human homologue of SAPAP3 a gene associated with
compulsive grooming in mice) was examined. Several SNPs
were nominally associated with OCD, although none survived
correction for multiple testing. Finally, preliminary results of
genome-wide association studies for OCD and TD will be
presented. Two-thousand-five-hundred OCD-affected
individuals and 1,800 TD-affected individuals were genotyped
using the Illumina Human610 Beadchip. Preliminary results
suggest that at least two TD loci are associated with p-values
less than 10-8-10-9. To date, no OCD loci have achieved
genome-wide significance, but several were associated with
p-values in the 10-6-10-7 range. Results presented in this
symposium should help to advance our understanding of the
genetic etiologies of OCD and TD.

S10.2 LATENT STRUCTURE IN OBSESSIVE
COMPULSIVE DISORDER
C. Mathews* (1), M. Andresen (2), D. Cath (3), K. Delucchi
(1), D. Denys (5), H. Katerberg (6), C. Lochner (7), D. Stein
(7), S. Stewart (8)
1. UCSF 2. University of Minnesota 3. Utrecht 4. UCSF 5.
University of Amsterdam 6. University of Groningen 7.
University of Stellenbosch 8. Massachusetts General Hospital
* cmathews@lppi.ucsf.edu
Objective: Obsessive-compulsive disorder (OCD)
isphenomenologically heterogeneous, and data reduction
methods have been increasingly used to identify more
homogeneous subgroups, with varying results. We present the
results of factor and latent class analyses in a large
multi-center sample of OCD patients and their relevance to
genetics and treatment outcome. Method: Principal
components factor (PCA) and latent class analyses (LCA)
using obsessive-compulsive (OC) symptoms from the
Yale-Brown Obsessive-Compulsive Scale were conducted in
1200 and 1600 OCD-affected individuals, respectively.
Heritability of the resulting factors and relationships between
latent class membership and treatment response, gender,
symptom severity and comorbid tics were tested. Results:
PCA resulted in a five-factor model: 1) taboo, 2)
contamination/cleaning, 3)doubts, 4) superstitions/rituals, and
5) symmetry/hoarding. All factors except factor 4 were
heritable. LCA best-fit models yielded three or five classes.
Classes in the three-class solution differed only in frequency
of endorsement of symptoms, irrespective of symptom type.
The five-class solution was similar to the three-class, with the
addition of a minimal endorsement class and a class with
predominantly contamination/cleaning symptoms. Classes
with higher symptom endorsement were associated with
earlier age of onset, male gender, and comorbid tics. The
contamination/cleaning class was associated with improved
treatment outcome. Conclusions: These results provide
support both for the validity of OCD as a single diagnostic
entity with varying levels of severity/symptom endorsement,
and for additional separate, genetically distinct OC symptom
dimensions. The large size and heterogeneous nature of the
sample has the advantage of increasing the generalizability of
the findings.
S10.3 GENOME-WIDE ASSOCIATION STUDY OF
TOURETTE DISORDER IN EUROPEAN ANCESTRY
SAMPLES AND FOUR POPULATION ISOLATES
J. Scharf* (1), B. Neale (1), S. Service (2), A. Tikhomorov
(3), J. Fagerness (1), A. Pluzhnikov (3), D. Yu (1), J. Crane
(1), M. State (4), J. Tischfield (5), D. Cath (6), G. Rouleau (7),
A. Ruiz-Linares (8), C. Mathews (9), C. Sabatti (2), S. Purcell
(1), N. Freimer (2), N. Cox (3), D. Pauls (1), GENEVA
1. Massachusetts General Hospital 2. University of California,
Los Angeles 3. University of Chicago 4. Yale University 5.
Rutgers University 6. University of Utrecht, Netherlands 7.
University of Montreal, Canada 8. University College London,
England 9. University of California, San Francisco
* jscharf@partners.org
Tourette Disorder (TD) is highly heritable, though no
definitive susceptibility genes have been identified. Here,
results from the first genome-wide association study (GWAS)
of TD in 1,749 cases and 4,410 ancestry-matched controls will
be reported. Cases included 983 subjects of European ancestry
(EA) as well as 766 subjects from four population isolates:
French Canadian (FC), Ashkenazi Jewish (AJ), Antioquia
Colombian (CO) and Central Valley Costa Rica (CR).
Diagnoses were made using DSM-IV-TR criteria. Case
samples and population isolate controls from FC and CO were
genotyped on the Illumina Human610Quad Beadchip; EA and
AJ controls were previously genotyped on the Illumina
Human550K and Human317K Beadchips, respectively. QC
and population-stratified analyses were performed in PLINK.
Preliminary results are based on analysis of 95% of the data.
After standard QC to remove poorly performing SNPs and
individuals, 1552 cases and 4027 controls remained.
Multi-dimensional scaling was performed to control for
population substructure; population outliers were excluded.
Data were analyzed using logistic regression under an additive
model with significant MDS axes included as covariates.
Preliminary association analysis identified 8 loci with genomic
control-adjusted p-values in the 10-7-10-9 range (seven in the
EA sample and one in the AJ sample). In the FC and CR/CO
populations, no loci had GC-adjusted p

S10.4 A GENOME-WIDE ASSOCIATION STUDY OF
OBSESSIVE-COMPULSIVE DISORDER
S. Stewart* (1), B. Neale (1), J. Fagerness (1), C. Mathews
(2), J. Knowles (3), P. Arnold (4), G. Hanna (5), D. Cath (6),
D. Denys (7), A. Hounie (8), M. Wagner (9), C. Lochner (10),
M. Cavallini (11), H. Nicolini (12), D. Murphy (13), G.
Nestadt (14), S. Purcell (1), D. Pauls (1)
1. Massachusetts General Hospital 2. University of California,
San Francisco 3. University of Southern California 4.
University of Toronto 5. University of Michigan 6. Utrecht
University 7. University of Amsterdam, Institute for
Neuroscience 8. University of São Paulo 9. University of
Bonn 10. Stellenbosch University 11. Fondazione Centro San
Raffaele del Monte Tabor 12. Universidad Autónoma de la
Ciudad de México 13. National Institute of Mental Health 14.
Johns Hopkins University
* stewart@pngu.mgh.harvard.edu
Introduction: Obsessive-Compulsive Disorder (OCD) is a
complex genetic illness. This first genome-wide association
study (GWAS) of OCD included European ancestry cases &
family trios from the OCF Genetics Collaborative. Methods:
1558 OCD cases of European ancestry and 477 OCD trios
were included, as diagnosed via DSM-IV criteria. OCD
samples were genotyped on the Illumina Human610Quad
Beadchip; 3, 212 European ‘iControl’ samples were
previously genotyped on the Illumina Human550K Beadchip.
QC & stratified analyses were performed in PLINK. TDT &
case-control samples were weighted by power. GPC based
non-centrality parameters were employed. A weighted Z
approach transformed P into Z-values for combining the
samples. Results/Conclusions: Standard QC removed poorly
performing SNPs & individuals, leaving 1558 cases. Checks
for familial relationship and Mendel errors left 477 trios.
Multi-dimensional scaling (MDS) was performed to exclude
population outliers and to be included as covariates in logistic
regression analyses under an additive model. Combining these
two datasets yielded a genomic control ? of 1.09. Preliminary
analyses identified two loci with p-values in the 10-7 range &
12 loci with p-values in the 10-6 range. Four of the top 14
associated genes are involved in glutamate neurotransmission
(GRK4, GRID2, GRIN2B & DLGAP1), consistent with
current etiologic theories of OCD and previous candidate gene
studies. Although results of this first GWAS study of OCD
were promising, with multiple biologically plausible
associated loci, results fell short of genome-wide significance.
Additional genotyping in independent samples will be
necessary to confirm these findings.
S10.5 DLGAP3 AND OBSESSIVE-COMPULSIVE
DISORDER
P. Arnold* (1), S. Stewart (2), S. Shaheen (1), J. Fagerness
(2), S. Taillefer (1), B. Doan (1), A. Hounie (3), J. Kennedy
(4), E. Cook (5), D. Pauls (1), M. Richter (6), C. Mathews (7),
G. Hanna (8)
1. Hospital for Sick Children 2. Massachusetts General
Hospital 3. University of Sao Paulo 4. Centre for Addiction
and Mental Health 5. University of Illinois at Chicago 6.
Sunnybrook Health Sciences Centre 7. University of
California at San Francisco 8. University of Michigan
* paul.arnold@sickkids.ca
A recently described putative animal model of
obsessive-compulsive disorder (OCD) is the SAPAP3 (human
homologue DLGAP3) knockout mouse, which exhibits
compulsive grooming behaviour and corticostriatal glutamate
transmission dysregulation. We hypothesized that a significant
association would be identified between DLGAP3 and OCD
using a family-based association approach. Tag single
nucleotide polymorphisms (SNPs) were selected using
publicly available databases (dbSNP, HapMap) and the
Haploview program. The sample comprised OCD-affected
probands and their first degree relatives from a combined
sample of 1575 individuals (308 families), recruited from
specialized OCD clinics by investigators at six sites (Toronto,
Michigan, Boston, Paris, San Francisco, and Brazil).
Genotyping was performed on the Sequenom iPlex platform.
Markers with genotyping success rates < 90%, with minor
allele frequency < 0.05, with greater than 10 Mendelian errors
were excluded, leaving a set of 26 markers for analysis. Single
marker and haplotype analyses were conducted using FBAT
(Family Based Association Test) and Haploview software. In
the whole sample, several SNPs were nominally associated
with OCD, although none remained significant after
permutation testing. Exploratory analysis stratified by gender
revealed that one SNP lying 5’ of the gene, rs16837122 was
significantly associated (p = 0.003, not corrected for multiple
testing) when examining transmission to male rather than
female probands. Consistent with findings reported from other
glutamate system genes (e.g. the glutamate transporter
SLC1A1), these preliminary findings suggest a possible
gender-specific association between sequence variation in or
near the DLGAP3 gene and OCD in males.

S10.6 GENOME-WIDE LINKAGE ANALYSES OF
COSTA RICAN FAMILIES WITH OBSESSIVE
COMPULSIVE DISORDER
J. Ross* (1), A. Azzam (1), D. Chavira (2), C. Mathews (1),
H. Garrido (3)
1. Department of Psychiatry, Langley Porter Psychiatric
Institute, UCSF, San Francisco, CA 2. Department of
Psychiatry, UCSD, La Jolla, CA 3. Department of Psychiatry
and Pediatrics, University of Costa Rica School of Medicine,
San Jose, Costa Rica
* jross@lppi.ucsf.edu
Introductions: Obsessive Compulsive Disorder(OCD) is a
complex neuropsychiatric disorder with a prevalence of 1-2%
in most populations, and a component of heritability
demonstrated through , twin, and segregation studies.
Published OCD linkage studies have identified several
possible susceptibility loci, pointing to both a complex genetic
architecture and genetic heterogeneity. Methods: Extensive
clinical information and DNA samples were ascertained from
28 families from both Central Valley of Costa Rica and the
US, but as initial linkage analysis revealed that these were two
distinct genetic populations with regards genetic etiology for
OCD, they were analyzed separately. These are the results of
parametric non-parametric(NPL) linkage of 3
multi-generational families from Cost Rica with multiple
members with OCD. Individuals were genotyped using the
Illumina Linkage Panel IV(approximately 5800 markers).
Linkage analyses were done using MERLIN and
SIMWALK2snp. Significance analyses were also completed.
Results: Initial linkage analysis revealed that NPL scores over
1.5 on chromosomes several chromosomes, with a maximum
NPL of 2.8. Several loci identified, including the one with the
maximum NPL score, were in close proximity to loci
identified in prior published OCD genome wide linkage
studies. Bioinformatic pathway analysis of genes with max lod
scores over 1.5 identified 11 genes at these loci that were
involved in neurodevelopmental pathways that had less than 2
degrees of separation. Discussion: The results of this study
provide additional evidence of several genetic loci conferring
susceptibility to OCD, and suggest neurodevelopmental
pathways where several loci may interact in the pathology of
this disease.
S10.7 TIC SYMPTOM DIMENSIONS AND THEIR
HERITABILITY IN TOURETTE’S SYNDROME
M. de Haan (1), K. Delucchi (2), D. Cath* (3), C. Mathews
(2)
1. Department of Psychiatry, VU University 2. Department of
Psychiatry, UCSF 3. Department of clinical psychology,
Utrecht University
* cath@xs4all.nl
Objective: Gilles de la Tourette’s disorder (GTS) is both
genotypically and phenotypically heterogeneous. Factor
analytic strategies to reduce symptom heterogeneity are useful
for unravelling heritability patterns and genetic susceptibility
genes for GTS. Method: A self-report questionnaire for
multiple tic symptoms was collected in two large Caucasian
cohorts (UCSF San Francisco; VU University Amsterdam),
totalling 494 patients. Item-level factor analysis using a
tetrachoric correlation matrix in Mplus version 5.1 was
conducted on twenty-six tic symptom variables that
overlapped between the two samples. Heritability analysis was
conducted for the resulting symptom dimensions using
Sequential Oligogenic Linkage Analysis Routine (SOLAR) in
a subset of subjects and their family members. Results: Three
factors were identified: 1) Complex vocal tics & obscene
behaviour; 2) Motor body tics; and 3) Motor head tics. The
heritability analysis showed moderate heritability (h2= 10%),
for factor 3 only. Conclusion/Discussion: The factor analytic
results of this study are in line with a previous category-based
FA study (Robertson et al., 2008) and a Latent Class Analytic
study (Mathews et al., 2007). The heritability analyses suggest
that the tic symptom dimension encompassing simple facial
motor tics is heritable. These findings have consequences for
future genetic studies in GTS, although the findings need
replication in independent samples.

S11 PHARMACOGENETICS OF
PSYCHIATRIC TREATMENTS – ARE WE
READY FOR THE CLINIC?
S11.1 PHARMACOGENETICS OF ATYPICAL
ANTIPSYCHOTIC EXPOSURE, FOLATE
METABOLISM, CARDIOVASCULAR DISEASE, AND
ENDOTHELIAL FUNCTIONING
V. Ellingrod* (1), T. Grove (1), S. Taylor (1), J. Moline (2),
D. Miller (3)
1. University of Michigan College of Pharmacy and School of
Medicine, Department of Psychiatry 2. Cleveland Clinics 3.
University of Iowa Carver College of Medicine, Department
of Psychiatry
* vellingr@umich.edu
Purpose: To examine the relationship between the
methylenetetrahydrofolate reductase (MTHFR) 677C/T
variant, metabolic syndrome, and endothelial functioning in
schizophrenia and bipolar subjects receiving antipsychotics for
≥ 6 months. Methods: 157 subjects were recruited from the
Universities of Iowa and Michigan and screened
cross-sectionally for the metabolic syndrome (NCEP ATP-III
criteria), MTHFR genotype, plasma folate, vitamin B12,
homocysteine, and endothelial functioning. Results: 60
subjects (37%) met metabolic syndrome criteria. The group’s
mean age (± s.d.) was 41.75 ± 11.65 years, 81% were
Caucasian, 52% were male, mean BMI was 31.04 ± 7.53
kg/m2 and 68% were receiving an atypical antipsychotic
(AAP). There were no differences in age, gender, race, AAP
exposure, or BMI between the genotype groups. Overall, a
significant relationship was found between the TT genotype,
AAP use, and metabolic syndrome (c2 = 6.44, p = 0.011). TT
subjects receiving an AAP had a relative risk of 2.27 (95% CI:
1.52-3.37) for metabolic syndrome. This was not found for
subjects not receiving AAPs (c2 = 0.617, p = 0.43). Higher
plasma folate concentrations resulted in lower homocysteine
levels for the CC genotype group, whereas no relationship was
found for T allele carriers (F = 6.971, df = 3,88, p = 0.0003).
Data analysis for the endothelial functioning suggests higher
folate plasma concentrations positively correlate with better
endothelial functioning. Conclusion: Overall, results suggest
that MTHFR genotype, AAPs exposure and folate, may be
associated with metabolic complications and CVD in
schizophrenia and bipolar subjects. However, due to the small
sample size results should be taken cautiously.
Acknowledgements: This project was supported by the NIMH
(K08 MH64158), the NIH-NCRR, General Clinical Research
Centers Program (M01-RR-59 and UL1RR024986), a
University of Michigan College of Pharmacy Vahlteich
Award, National Alliance on Research in Schizophrenia and
Depression (NARSAD), and Washtenaw Community Health
Organization (WCHO).
S11.2 VARIANTS OF ABC TRANSPORTERS:
CURRENT RELEVANCE IN PSYCHIATRY
L. DeVane (1)
1. Medical University of South Carolina
* devaneL@musc.edu
In addition to their role in gastrointestinal drug absorption,
hepatic, and renal elimination, several ABC transporter
proteins are expressed in tissues where their activity
can influence the efficacy and safety of psychoactive drugs.
These include P-glycoprotein (P-gp), breast cancer resistance
protein (BCRP), multidrug resistance proteins 1-3 (MRP1-3),
and others localized in endothelial cells of cerebral capillaries
comprising the blood brain barrier (BBB). A similar cadre of
transporters in trophoblastic cells of the placenta modify fetal
drug exposure during pregnancy, a period of great concern for
the pharmacologic treatment of mental illness. About 35% of
women take at least one psychoactive drug during their
pregnancy. The major antipsychotic and antidepressant drugs,
and opioid analgesics, are substrates for one or more of these
transporters. In rodents, both induction and inhibition of
transporter activity can be shown to affect brain and fetal
exposure to psychoactive drugs as well as producing
alterations in relevant pharmacologic activity. Emerging data
support the choice of specific psychoactive drugs for clinical
use should consider both their ABC transporter substrate
status as well as patient genotype for transporter expression.

S11.3 PHARMACOGENETICS OF SSRI ASSOCIATED
SEXUAL DYSFUNCTION AND MEDICATION
INTOLERANCE
J. Bishop* (1)
1. Departments of Pharmacy Practice and Psychiatry,
University of Illinois at Chicago
* jbishop@uic.edu
Sexual dysfunction is a common and disconcerting side effect
of selective serotonin reuptake inhibitors (SSRIs) that
influences a patient’s desire to continue long-term
antidepressant treatment. Studies specifically assessing
changes in sexual well-being over time illustrate that the
incidence of sexual side effects from SSRIs ranges from 20 to
70% depending on the characteristics of the study sample
assessed. Developing strategies to predict who may be at the
highest risk for adverse changes in their sexual well-being is
an important step in improving the quality of life and
treatment of patients who require antidepressant agents.
Although initial studies investigating antidepressant
pharmacogenetics focused on predicting treatment response,
an increasing number of studies have recently focused on
identifying genetic markers of medication intolerance. Studies
investigating medication intolerance in general, as well as
more specific lasting side-effects such as sexual dysfunction
have identified common genetic variations in serotonin and
glutamate system genes along with clinical variables that may
predict risk for these outcomes in patients taking
antidepressants. The results of studies investigating genetic
variations in drug metabolism enzymes and their relationships
to antidepressant-associated adverse effects have been mixed.
Continued efforts to identify the relationships between genetic
markers and antidepressant outcomes and to translate this
knowledge to patient care has the potential to significantly
improve the empiric selection of antidepressant agents and to
minimize the risk for intolerable side effects that may
compromise long term treatment.
S11.4 VARIANTS OF THE SEROTONIN SYSTEM AND
BONE MINERALIZATION IN BOYS TREATED WITH
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
C. Calarge* (1), V. Ellingrod (2), M. Bliziotes (3), W.
Coryell (1)
1. University of Iowa 2. University of Michigan 3. Oregon
Health and Science University
* chadi-calarge@uiowa.edu
Objective: To investigate whether genetic variants of the
serotonin (5HT) system moderate the effect of selective
serotonin reuptake inhibitors (SSRIs) on bone mineral density
(BMD) in boys. Methods: Healthy, 7-17 year-old
non-Hispanic Caucasian boys, treated with risperidone for ≥ 6
months, were included in this analysis. We measured BMD at
the lumbar spine using dual x-ray absorptiometry and total and
trabecular BMD at the distal radius using peripheral
quantitative computerized tomography. Genotyping of
selected polymorphisms of the genes transcribing the 5HT
transporter (5HTTLPR and Stin2 VNTR) and 5HT receptors
1A (A(-1019)C), 1B (G861C), 1D (T1350C), and 2A
(A(-1438)G) was done following standard procedures.
Results: The mean age of the sample was 12.1 years
(SD=2.7). Of 71 boys enrolled, 41 (58%) received an SSRI
for a median of 3.1 years (IQR=2.9). SSRI-treated boys were
less physically active and more likely to have a depressive, an
anxiety, or a pervasive developmental disorder compared to
those not taking SSRIs. Using multiple linear regression
analysis, after controlling for the relevant covariates, we found
a trend for the 5-HTTLPR genotype x SSRI treatment
interaction effect to be significant in predicting lumbar spine
BMD Z-score (p=0.055). In fact, the largest detrimental effect
of SSRIs on the lumbar BMD Z-score was noted among boys
with the ‘ls’ genotype (Cohen’s d= 1.04, p

S11.5 CYP450 GENOTYPING IN THE CLINICAL USE
OF ANTIPSYCHOTIC AND ANTIDEPRESSANT DRUG
TREATMENT
D. Müller* (1), R. Hwang (2), A. Tiwari (2), J. Sturgess (1),
C. Zai (2), J. Lieberman (3), P. Richter (4), J. Kennedy (2)
1. Pharmacogenetics Research Clinic, Centre for Addiction
and Mental Health, Toronto, Canada 2. Neurogenetics Section,
Centre for Addiction and Mental Health, Toronto, Canada 3.
Dept. of Psychiatry, Columbia University, NY 4. Sunnybrook
Health Sciences Center, Toronto
* daniel_mueller@camh.net
Introduction: A substantial number of antidepressant and
antipsychotic medications are metabolized by the liver
cytochrome P450 enzymes (CYP450) CYP2D6 and
CYP2C19. An individual’s genetic makeup allows for
classification by phenotype as poor (PM), intermediate (IM),
extensive or normal (EM), or ultra rapid drug metabolizers
(UM). The AmpliChip CYP450 Test provides genotyping
of CYP2D6 and CYP2C19 enzymes using microarray
technology which combines DNA hybridization with
fluorescent labeling. Methods: In our study we used 74
AmpliChips to analyze for an association
between metabolizer with response pattern to antipsychotics (n
= 23) and occurrence of tardive dyskinesia (TD; n = 12) in
patients with schizophrenia as well as response to
antidepressants in a sample of patients affected with OCD (n =
39). Medical records were also reviewed in cases who were
non-extensive metabolizers to assess the individual course of
treatment response and side effects. Response was assessed
with clinical assessment scales such as CGI and
PANSS whereas severity of TD was assessed by using AIMS
scores. Results: Most patients were extensive metabolizers
limiting statistical power. Overall, no association could be
detected between patients' metabolizer status and response to
antipsychotics, antidepressants or TD occurrence. However, a
significant association was observed in patients who
were CYP2D6 rapid metabolizers and non-response in
treatment trials with various CYP2D6 metabolized
antidepressant (p = .006). Conclusion: Our results suggest that
genotyping of CYP450 genes is a useful tool to optimize
clinical drug treatment for particular individuals.
S12 UNDERSTANDING NORMAL
VARIATION IN BRAIN STRUCTURE AND
FUNCTION WILL
INFORM PSYCHIATRIC GENETICS
S12.1 HERITABILITY OF FMRI RESPONSE IN
YOUNG ADULT TWINS
N. Martin* (1)
1. Queensland Inst Medical Research
* nick.martin@qimr.edu.au
While structural MRI studies consistently show a moderate to
strong influence of genes on brain structure, it is largely
unknown to what extent individual differences in neural
activity, as captured by fMRI, are influenced by genetic and
environmental factors. Working memory related brain
activation has been widely studied using the N-back working
memory task, and inefficient or abnormal function is evident
in several neurodegenerative and neuropsychiatric disorders,
and in the healthy siblings of patients for some disorders.
Deficits in physiological function may be therefore not only
associated with a disease, but also may reflect familial
(possibly genetic) factors predisposing to the disorder. Using a
regions of interest analysis we investigated the heritability of
brain activation during the N-back working memory task in a
sample of 120 young adult twins and provided the first support
that individual variation in working memory related brain
activation is to some extent influenced by genes, with
(non-significant) heritability estimates (14-30%) in the
low-moderate range. Most recently we have extended this to a
voxel-by-voxel analysis in a much larger sample (315 twins).
Overall the MZ twin correlations are significantly larger than
the DZ correlations, and there is good test-retest reliability for
a sub-sample (N=40) of twins that were scanned twice. Our
work establishes that there are significant genetic influences
on working memory brain activation, and that there are also
sizeable environmental effects on brain activation, which are
largely due to unique environmental factors rather than
measurement error.

S12.2 GENETIC ANALYSIS FOR NORMAL
VARIATION IN COGNITION, SLEEP AND SEASONAL
RHYTHMS: EXPERIENCES FROM TWIN AND
POPULATION-BASED STUDIES FROM FINLAND
T. Paunio* (1)
1. Public Health Genomics Unit, National Institute for Health
and Welfar
* tiina.paunio@thl.fi
Understanding genetic background for normal variation in
brain structure and function is likely to provide insight into
illnesses associated with related processes, such as impaired
cognition in schizophrenia or disturbed sleep in mood
disorders. We evaluated the contribution of AKT1, encoding
the protein kinase B and previously associated with the genetic
etiology of schizophrenia and bipolar disorder, to cognition
and brain structure in a Finnish twin sample comprising both
control pairs as well as pairs affected with schizophrenia or
bipolar disorder. We found association of an AKT1 allele
defined by a variation in the UTR with verbal learning and
memory (P = 0.0005) and, moreover, a higher degree of
resemblance in pairs sharing the genotype. The same allele
also associated with decreased gray matter density in medial
and dorsolateral prefrontal cortex, suggesting that and AKT1
may exert its effect on verbal cognitive processes via neural
networks involving prefrontal cortex (Pietiläinen et al,
2009).In an approach ultimately aiming to reveal genetic
background for disturbed mood, we searched for genetic
influences determining variation in sleep, known to be
affected in most patients with a mood disorder. In our previous
study in Finnish twins we found that depressed mood, as
measured by life dissatisfaction, predicted a consistent pattern
of life dissatisfaction (OR = 2.1), whereas life dissatisfaction
did not consistently predict poor sleep. The shared genetic
component between sleep quality and life dissatisfaction was
relatively weak, consistent with the hypothesis that poor sleep
may have direct effects on the brain, emotions, and mood
(Paunio et al. 2009). We then searched for genetic background
for variation in normal sleep length and seasonal rhythms in
2200 Finnish individuals from a population-based Health 2000
project by a genome-wide DNA association analysis. We
found several new genes and variants that associated to total
sleep length. Interestingly, the gene ontology analysis showed
that sleep length and seasonal changes in mood share common
genes and molecular pathways. Altogether, the data evidences
for a strong genetic background for variation in normal sleep
and seasonal rhythms and the findings will have implication in
our understanding patophysiological processes of common
diseases related to disturbed sleep, such as mood disorders.
Acknowledgments: Pietiläinen OP, Loukola A,
Tuulio-Henriksson A, Kieseppä T, Thompson P, Toga AW,
van Erp TG, Silventoinen K, Soronen P, Hennah W, Turunen
JA, Wedenoja J, Palo OM, Silander K, Lönnqvist J, Kaprio J,
Cannon TD, and Peltonen L for the study on AKT1 in twins;
Korhonen T, Hublin C, Partinen M, Kivimäki M, Koskenvuo
M, and Kaprio J. for the analysis of life dissatisfaction and
sleep quality in twins; Ollila HM, Partonen T, Kronholm E,
Männistö S, Lönnqvist J, Salomaa V, Peltonen L, Perola M,
and Porkka-Heiskanen T for the study on sleep length and
seasonal rhythms in Health 2000; Academy of Finland (grant
124404 to Paunio T) References: Pietiläinen OP, Paunio T,
Loukola A, et al. (2009) Association of AKT1 with verbal
learning, verbal memory, and regional cortical gray matter
density in twins. Am J Med Genet B Neuropsychiatr Genet.
2009 Jul 5;150B(5):683-92. Paunio T, Korhonen T, Hublin C,
et al. (2009) Longitudinal study on causality and genetic risk
factors for the association between poor sleep and life
dissatisfaction in a nationwide cohort of twins. Am J
Epidemiol. 169(2):206-13.
S12.3 A GENETIC INVESTIGATION OF
SCHIZOPHRENIA ENDOPHENOTYPES IN A
NEPALESE POPULATION GENETIC ISOLATE
T. Sitnikova (1), M. Hall (2), J. Subedi (3), S. Ojha (4), S.
Park (5), J. VandeBerg (6), J. Blangero (6), S.
Williams-Blangero (6), S. Santangelo* (1, 7)
1. Harvard Medical School, Dept Psychiatry, Boston, MA,
USA 2. Psychology Research Laboratory, McLean Hospital,
Belmont, MA, USA 3. Miami University, Dept. Sociology,
Gerontology, Oxford, OH, USA 4. Tribhuvan University
Institute of Medicine, Dept. Psychiatry, Kathmandu, Nepal 5.
Dept. Psychology Vanderbilt University, Nashville, TN, USA
6. Southwest Foundation for Biomedical Research, San
Antonio, TX, USA 7. Center for Human Genetic Research,
Massachusetts General Hospital, Boston, MA, USA
* ssantangelo@pngu.mgh.harvard.edu
Schizophrenia endophenotypes were measured in a population
genetic isolate in Jiri, Nepal, encompassing over 2500
surveyed individuals in one extended pedigree. This is both an
epidemiological sample (complete ascertainment of 4 of 7
villages) and a pedigree sample. The amplitude and latency of
the N100, N200, and P300 electrophysiological evoked
potentials (ERPs), as well as the power of evoked and induced
oscillatory brain activity in the gamma-band range (35-45Hz),
were measured during an auditory "oddball" paradigm. The
P50 ERP amplitude was measured in a double-click paradigm.
In addition, performance was tested on cognitive tasks,
including go-no-go, set shifting, strategic target detection, and
spatial working memory. Several other tasks in the original
battery were discontinued when they were found to be
excessively language- or culture-bound. Data collection just
ended, and data are being analyzed for the 960 individuals
who participated in these studies. Each of the heritable
measures is subjected to a genome-wide linkage analysis,
using a 10 cM microsatellite marker set. A new genome scan,
using the Illumina v. 610 SNP array, is in progress. Analysis
of the cognitive test data is ongoing. However, we found
significant linkage to at least one of the ERPs (P300 amplitude
measured at the Pz electrode, at chromosome 2p15, reported
elsewhere at this meeting) and suggestive linkage to others
(e.g. induced gamma measured at the P4 electrode at 2p13).
Genes in this region include sepiapterin reductase, an enzyme
required forsynthesis of tetrahydrobiopterin (BH4), an
essential cofactor for synthesis of many neurotransmitters,
including serotonin.

S12.4 GENOME-WIDE COMBINED
LINKAGE/ASSOCIATION SCAN LOCALIZES TWO
QTLS INFLUENCING HUMAN CAUDATE NUCLEUS
VOLUME
D. Glahn* (1), A. Winkler (1), J. Curran (2), M. Carless (2), J.
Charlesworth (2), M. Johnson (2), H. Göring (2), T. Dyer (2),
E. Moses (2), L. Almasy (2), P. Fox (3), P. Kochunov (3), R.
Duggirala (2), J. Blangero (2)
1. Yale University & Olin Neuropsychiatric Research Center,
Institute of Living 2. Department of Genetics, Southwest
Foundation for Biomedical Research 3. Research Imaging
Center, UT Health Science Center at San Antonio
* david.glahn@yale.edu
The caudate nucleus (CN), a brain region located within the
basal ganglia, is associated with higher-order motor control,
learning and memory, feedback processing, language and
other executive functions. The CN, which is innervated by
dopaminergic neurons, is thought to be a locus of pathology
for several neurological and psychiatric disorders (e.g.
Schizophrenia and Bipolar Disorder). While the size and
function of the CN are thought to be under genetic control, the
genes influencing the volume of this brain region are
unknown. To better understand the genetic basis of CN
volume variation in the normal population, we undertook the
first large-scale genome-wide search for genes influencing
human brain structure. We collected high-resolution
T1-weighted MRI scans from approximately 400
Mexican-American individuals from 30 extended pedigrees
who participated in the Genetics of Brain Structure and
Function study and who have Illumina HumanHap 550K SNP
genotyping available. Imaging data was analyzed with
FreeSurfer and genetic analyses were performed with SOLAR.
The heritability of CN volume was estimated to be 0.685
(p=2.3×10-10). Combined linkage/association analysis
identified two regions exhibiting genome-wide significant
evidence for harboring QTLs influencing caudate volume.
One QTL was localized on chromosome 7p22 with a strongly
associated SNP in the PRKAR1B gene (nominal p-value =
2.3×10-8, genome-wide p-value = 0.02). This gene codes for
the protein kinase, cAMP-dependent, regulatory, type I, beta,
which is involved in brain development and linked to poor
memory. Examination of the potential pleiotropic associations
of this SNP with neurocognitive function revealed significant
associations with processing speed (p = 0.005), episodic
memory (p = 0.04) and working memory (p=0.05). Thus, this
QTL appears to influence both brain structure and function. A
second QTL influencing caudate volume was localized to
chromosomal region 2p12 with strong association to a SNP
near the LRRTM4 gene (nominal p-value = 1.3×10-7,
genome-wide p-value = 0.049) which codes for a neuronal
protein of unknown function. Given the strength of these
signals, we are currently deeply sequencing these genes to
identify potential functional variants. Dissection of the genetic
basis of normal human brain structural variation should lead to
the identification of genes likely to be involved in disorders of
brain structure/function.
S12.5 GENOMIC AND TRANSCRIPTOMIC
APPROACHES TO IDENTIFYING GENES
INFLUENCING COGNITION AND NEUROANATOMY
L. Almasy* (1), M. Carless (1), J. Curran (1), M. Zlojutro (1),
H. Goring (1), T. Dyer (1), R. Duggirala (1), D. Glahn (2), J.
Blangero (1)
1. Southwest Foundation for Biomedical Research, San
Antonio, TX, USA 2. Yale University, New Haven, CT, USA
* almasy@sfbrgenetics.org
This presentation will discuss the rationale for studying
normal variation in brain structure and function and how such
studies provide insight into genetics of psychiatric disorders.
Examples will be provided from the Genetics of Brain
Structure and Function Study, which makes use of an existing
resource of large Mexican American families in San Antonio,
Texas, for which a GWAS and genome-wide transcription
profiling in lymphocytes have already been completed.
Individuals from these families are currently being recalled for
cognitive testing, structural MRI, and psychiatric screening.
Currently this data is available for 1000 individuals. This
resource is being used to 1) document heritability of potential
psychiatric endophenotypes; 2) assess pleiotropic influences
among these quantitiative risk factors and between
endophenotypes and high prevalence disorders such as
depression and substance abuse; 3) localize genes influencing
normal variation in brain structure and function in which
other, more extreme, genetic variants might influence risk of
psychiatric disorder; 4) identify upstream genes regulating
expression of previously identified genes important for
psychiatric phenotypes; 5) identify downstream genes whose
expression is regulated by genes of interest for psychiatric
disorders.

S13 ANOREXIA NERVOSA – GENES OR
JEANS
S13.1 A GENOME-WIDE ASSOCIATION STUDY IN
PATIENTS WITH ANOREXIA NERVOSA
K. Wang* (1), H. Zhang (1), C. Bloss (2), N. Schork (2), W.
Berrettini (3), H. Hakonaron (1), P. Collaborative Group (4)
1. Children's Hospital of Philadelphia 2. Scripps Translational
Science Institute 3. University of Pennsylvania 4. Price
Foundation
* tumorim@gmail.com
Anorexia nervosa (AN) is a serious psychiatric illness
characterized by restricted eating and obsessive fears of being
fat, with an inability to maintain a normal healthy body
weight. The current prevalence estimates ranged from 0.1% to
5.7% in female subjects in Western countries. The heritability
of anorexia is estimated to be 56%, with sibling relative risk of
11.3, implicating a strong genetic component in anorexia
susceptibility, most of which remains uncovered. To identify
genetic risk factors for anorexia, we carried out a
genome-wide association study (GWAS) on 1,016 female
cases and 1,796 female control subjects, all of whom were of
European ancestry and were genotyped on the Illumina
HumanHap610 platform. The top association results were
examined in a separate cohort of 24 cases and 648 control
subjects of European ancestry genotyped on the
HumanHap550 platform. Several SNPs residing between
CDH10 (cadherin 10) and CDH9 (cadherin 9) – a locus
previously implicated in autism spectrum disorders -
demonstrated genome-wide significance (most significant
P=1.5x10-8). Analysis of previously reported AN-associated
SNPs replicated association with OPRD1 (rs1042114,
P=0.02), but failed to detect association with HTR1D
(rs7532266, P=0.83). Furthermore, nominal significance was
observed for SNPs near DRD2 (rs10891556, P=0.0023), near
HTR2A (rs7331274, P=0.0025), near HTR1B (rs6454038,
P=0.0048), within HTR7 (rs7920627, P=0.0048), near DRD3
(rs9825563 , P=0.0087), near CNR1 (rs9344757, P=0.0058),
but they do not survive corrections for multiple testing of
SNPs within or near each gene. Taken together, we have
identified a genome-wide significant locus in AN and
replicated OPRD1, demonstrating the utility of
whole-genome, unbiased survey in identifying novel genomic
regions and confirming previously reported candidate genes.
S13.2 GENOME-WIDE ASSOCIATION OF
PERSONALITY TRAITS IN INDIVIDUALS WITH
ANOREXIA NERVOSA
C. Bloss* (1), K. Wang (2), W. Berrettini (3), A. Bergen (4),
P. Magistretti (5), W. Kaye (6), H. Hakonarson (2), N. Schork
(1)
1. Scripps Translational Science Institute 2. Children's
Hospital of Philadelphia 3. University of Pennsylvania 4. SRI
International 5. University of Lausanne 6. University of
California, San Diego
* cbloss@scripps.edu
Several studies have shown that certain facets of personality
differ markedly between women with anorexia nervosa (AN)
and controls, as well as between women with different
subtypes of AN. As such, certain temperament traits have
been hypothesized to both predispose to AN, as well as predict
illness course and response to treatment. Given these
observations, coupled with the known moderate heritability of
temperament, we investigated the extent to which common
genetic polymorphisms may underlie aspects of personality in
this disorder by conducting a genome-wide association study
of the Temperament and Character Inventory (TCI) in women
with AN. Participants were n = 1,001 women with AN
enrolled in the Price Foundation Collaborative Study of
Anorexia and Bulimia Nervosa. Participants were all of
European ancestry and were administered the TCI and
genotyped on the Illumina HumanHap610 platform. In
addition to standard univariate quantitative trait association
analyses conducted with each temperament scale of the TCI,
several multivariate analytic approaches were also leveraged
to assess genetic association with TCI profiles. Standard
univariate analyses revealed different associations (p < 5 x
10-6) for each scale of the TCI, including SNPs near RNF165
for harm avoidance, ZNF645 for novelty seeking, BTG3 for
reward dependence, and RBAK for persistence. Furthermore,
analyses that included relevant covariates, as well as cluster
and other multivariate approaches identified additional regions
of interest. Findings suggest novel genes that may underlie
single dimensions of personality, as well as personality
profiles in anorexia nervosa.

S13.3 GENETICALLY MEDIATED, PRE-MORBID
VULNERABILITIES OF TEMPERAMENT AND
PERSONALITY IN ANOREXIA AND BULIMIA
NERVOSA
W. Kaye* (1)
1. University of California San Diego
* whkaye@gmail.com
Many individuals desire to diet and lose weight, but relatively
few develop an eating disorder. Recent studies show that
certain childhood temperament and personality traits such as
negative emotionality, harm avoidance, perfectionism,
inhibition, drive for thinness, altered interoceptive awareness,
and obsessive-compulsive personality, create a vulnerability
for developing anorexia nervosa (AN) and bulimia nervosa
(BN). Moreover, studies done on 3 continents have shown that
for AN and BN individuals with a lifetime history of an
anxiety disorder diagnosis, the anxiety disorder most often
began in childhood before the onset of the ED. Such
symptoms may be susceptibility factors that make people
vulnerable to developing an ED. Malnutrition tends to
exaggerate these premorbid behavioral traits after the onset of
the illness. The process of recovery in AN is poorly
understood and, in most cases, protracted. Still,
approximately 50% to 70% of affected individuals will
eventually have complete or moderate resolution of the illness,
often in the early to mid 20’s. It is important to emphasize
that temperament and personality traits such as negative
emotionality, harm avoidance and perfectionism, obsessional
behaviors (particularly symmetry, exactness, and order) persist
after recovery from both AN and BN and are similar to the
symptoms described premorbidly in childhood. Compared to
the ill state, symptoms in REC AN and BN tend to be mild to
moderate. Interestingly, REC AN and BN tend to be more
alike than different on many of these measures, although there
are some differences on factors related to impulse control or
stimuli seeking, such as novelty seeking. In summary,
individuals with restricting type AN are more likely to have
restricted eating, constricted affect and emotional mood
expression, and impulse over control, as well as personality
traits of marked rigidity, conformity, and reduced social
spontaneity. Individuals with BN may show similar traits, but
in addition, may exhibit histories of episodic overeating,
extremes of intense affect, and impulse dysregulation. AN
and BN most commonly develop during adolescence or young
adulthood 19 in proximity to puberty. Adolescence is a time
of profound biological, psychological and sociocultural
change, and it demands a considerable degree of flexibility to
successfully manage the transition into adulthood.
Psychologically, change may challenge the rigidity of those at
risk for AN and BN, and thus open a window of vulnerability.
Thus these vulnerabilities, which are biologically mediated,
may significantly enhance the risk of onset of an ED,
particularly in women.
S13.4 THE PRICE FOUNDATION STUDIES – A
RESOURCE FOR ANOREXIA NERVOSA RESEARCH
A. Bergen* (1), The Price Foundation Collaborative Group
1. SRI International
* andrew.bergen@sri.com
Over a period of ten years, a multinational collaboration
ascertained over 1000 unrelated individuals with a DSM-IV
diagnosis of anorexia nervosa in three separate studies
encompassing family (sib-pair and trio) and unrelated
collection methods, and nearly 700 unrelated individuals
screened for DSM-IV diagnoses. A series of linkage studies in
pedigrees and association analyses in both family based and
unrelated individuals have been published. In particular, a
series of linkage and association studies have identified
significant linkage in the chr1p34-36 region and association at
the genes coding for the delta opioid and 1D serotonin
receptors in samples ascertained by this collaboration and in
an independent sample. Despite this early example of a
replicated association, candidate gene association studies in
the world anorexia nervosa literature have been characterized
by less than optimal sample sizes and incomplete investigation
of gene variation at candidates. These limitations are being
addressed using candidate gene and genome wide association
approaches focusing on common variation, and candidate gene
resequencing studies focusing on both common and rare
variation, though limitations with respect to sample size and
power continue to influence this field in common with all
fields of genetic research, suggesting that additional
technologies and collaborations will be necessary to promote
further discovery. For example, biospecimens (DNA,
lymphoblastoid cell lines, viably frozen cells) from both
affected and unaffected individuals recruited in the Price
Foundation studies are available and offer the potential for
genetical genomics studies, with appropriate and extensive
control assessments to avoid confounding due to participant,
biospecimen processing, cell line and technical characteristics.

S13.5 LARGE-SCALE CANDIDATE GENE
RESEQUENCING IN ANOREXIA NERVOSA
A. Scott* (1), C. Bloss (1), S. Murray (2), R. Tewhey (3), V.
Bansal (1), O. Libiger (1), A. Torkamani (1), M. Shaw (2), J.
Bishop (4), T. Price Foundation Collaborative Group, P.
Magistretti (5), A. Bergen (6), W. Berrettini (7), A. Harris (8),
W. Kaye (9), E. Topol (2), N. Schork (2)
1. Scripps Translational Science Institute and The Scripps
Research Institute 2. Scripps Genomic Medicine, Scripps
Translational Science Institute and The Scripps Research
Institute 3. Divison of Biological Sciences, University of
California, San Diego and The Scripps Research Institute 4.
Life Technologies 5. Ecole Polytechnique Federale De
Lausanne, Switzerland6. Molecular Genetics, SRI
International 7. Center for Neurobiology and Behavior,
University of Pennsylvania 8. Life Technologies 9. Eating
Disorder Treatment & Research Program, Department of
Psychiatry, University of California, San Diego
* ashleys@scripps.edu
Anorexia nervosa (AN) is a complex psychiatric illness
characterized by restricted eating patterns and an intense fear
of weight gain. Current estimates place the incidence of AN
between 3 and 8 per 100,000 persons per year, affecting
women significantly more often than men. Although there is
evidence of significant heritability (0.58-0.76) and genetic
liability for anorexia, previous candidate gene and current
genome-wide association (GWA) studies have elucidated only
a small fraction of the genetic vulnerability for the disorder.
Therefore, we are undertaking a large-scale sequence-based
association study of anorexia to uncover highly penetrant rare
variants associated with the disorder. Over the past 15 years,
the Price Foundation has supported the collection of a large
cohort of individuals with AN. To discover additional genetic
variants that contribute to AN, we are resequencing
approximately 1 Mb of exomic DNA in 400 women with
restricting-subtype AN (RAN) and 100 control women using
the Life Technologies SOLiD next-generation sequencing
platform. Over 100 genes and genomic regions were selected
based on results from previous GWA and candidate gene
studies, as well as a priori neurobiologically relevant candidate
genes. Targeted capture and amplification of conserved and
exonic regions within these genes was performed using
RainDance microdroplet-based emulsion PCR. In addition to
case-control comparisons to identify sequence-based
associations with RAN, we are also investigating
neurobehavioral subclinical phenotypes within the RAN cases.
This study has the potential to provide new insights into the
spectrum of genetic variation in anorexia nervosa.
S14 SUB-PHENOTYPES AND MACRO-
PHENOTYPES IN MOOD DISORDERS
S14.1 APPROACHES TO ANALYZING GWAS DATA
IN BIPOLAR DISORDER USING INFORMATION
ABOUT ITS CLINICAL HETEROGENEITY
P. Zandi* (1), M. Pirooznia (2), P. Belmonte (2), F. Seiffudin
(2), J. Judy (2), T. Phenome Group, J. Potash (2)
1. Johns Hopkins University Bloomberg School of Public
Health 2. Johns Hopkins University School of Medicine
* pzandi@jhsph.edu
Family, twin and adoption studies show that genetic factors
play a significant role in the etiology of bipolar disorder.
However, recent genome-wide association studies (GWAS)
have yet to convincingly identify individual susceptibility
genes with large effects on risk. This may be due to the fact
that bipolar disorder is likely caused by multiple different
genes with small effect sizes acting in complex pathways to
illness. It is notable that bipolar disorder is clinically very
heterogeneous. For example, data suggests the age at onset
ranges anywhere from adolescence to old age with a median
between 18-21 years of age, and that up to 58% of bipolar
patients present with psychotic symptoms, 61% have a
substance abuse disorder, 53% suffer with a co-morbid anxiety
disorder, and 15% die from suicide. Some investigators have
proposed that this clinical heterogeneity may reflect the
underlying genetic heterogeneity of the disorder. Therefore,
analytic methods that utilize information about the clinical
heterogeneity of the disorder may facilitate the identification
of relevant susceptibility genes. We explore three different
genetic models that may explain how multiple genes
contribute to the apparent clinical heterogeneity of bipolar
disorder, including a heterogeneity model, a modifier model,
and an epistatic model. We examine approaches for analyzing
GWAS data to identify susceptibility genes and draw
inferences about the model for how they contribute to risk.
The approaches are compared through simulation and by
application to real data.

S14.2 A GENOME- WIDE ASSOCIATION STUDY OF
BIPOLAR DISORDER AND CO-MORBID MIGRAINE:
IDENTIFICATION AND REPLICATION OF GENETIC
ASSOCIATIONS IN THE 13Q14.1 REGION
HARBOURING THE GENE KIAA0564
K. Oedegaard* (1), T. Greenwood (2), S. Johansson (3), K.
Jacobsen (3), A. Halmoy (3), O. Fasmer (4), H. Akiskal (2, 5),
Bipolar Genome Study (BiGS), J. Haavik (9), J. Kelsoe (2, 5)
1. University of Bergen, Moodnet Research Group, Haukeland
University Hospital, Norway 2. Department of Psychiatry,
University of California San Diego, La Jolla, CA, USA 3.
Department of Biomedicine, University of Bergen, Norway 4.
Department of Psychiatry, University of Bergen, Norway 5.
Department of Psychiatry, VA San Diego Healthcare System,
La Jolla, CA, USA
* keti@haukeland.no
Both migraine and Bipolar Disorder (BPAD) are complex
phenotypes with significant genetic and non-genetic
components. Epidemiological and clinical studies have
demonstrated a high degree of co-morbidity between migraine
and BPAD. Numerous genome- wide linkage studies in BPAD
and migraine have shown overlapping regions of linkage on
chromosomes, and two functionally similar voltage-dependent
calcium channels, CACNA1A and CACNA1C, have been
identified in familial hemiplegic migraine and recently in three
BPAD genome-wide association studies (GWAS),
respectively. To identify susceptibility factors for the
BPAD/migraine phenotype, we conducted a GWAS in 1001
cases with bipolar disorder collected through the Foundation
for the National Institutes of Health Genetic Information
Association Network (GAIN) initiative. We compared BPAD
patients without any headache (n= 699) to BPAD patients with
doctor diagnosed migraine (n=56). The strongest evidence for
association was found for several SNPs in a 317 kb region
encompassing the uncharacterized gene KIAA0564 (e.g.
rs9566845 (OR=4.98 (95%CI: 2.6-9.48), p= 7.7 x10-8 ) and
rs9566867 (p= 8,2 x 10-8 )). Furthermore, marker rs9566845
was genotyped and found associated with migraine in an
independent Norwegian sample of adult ADHD patients with
and without co-morbid migraine (n=131 and n=324
respectively), OR=2.42 (1.18-4.97), p=0.013. In conclusion,
this is the first GWAS examining patients with bipolar
disorder and co-morbid migraine, and the first migraine
GWAS in any sample. Together these data suggest that
genetic variants in the KIAA0564 gene region may predispose
to migraine headaches in subgroups of patients with both
BPAD and ADHD.
S14.3 A GENOME-WIDE ASSOCIATION STUDY OF
AGE AT ONSET IN A COMBINED BIGS/GERMAN
BIPOLAR DISORDER SAMPLE
P. Belmonte (1), D. Jancic (1), T. Schulze (2), Bipolar
Genome Study (BiGS), S. Cichon (3), M. Nothen (3), R.
Breuer (4), F. McMahon (2), M. Rietschel (4), J. Potash* (1),
P. Zandi (5)
1. Johns Hopkins School of Medicine 2. National Institute of
Mental Health 3. Life and Brain Center, University of Bonn 4.
Central Institute of Mental Health, Mannheim 5. Johns
Hopkins Bloomberg School of Public Health
* jpotash@jhmi.edu
Age at onset of bipolar disorder (BP) aggregates in families,
with affected relatives of early onset probands being 4.5 times
more likely than others to have early onset themselves.
Linkage regions related to age at onset in BP have been
identified on chromosomes 21q22 and 18p11. We initially
examined age at onset data from a genome-wide association
study of BP in the Genetic Association Information Network
(GAIN) BP sub-sample of the Bipolar Genetics Study
(BiGS). This sample consisted of 1,034 controls and 1,001 BP
cases, of whom 681 have early onset (age at onset ≤ 21) and
285 have late onset (age at onset > 21). Genotyping was
performed using Affymetrix Genome-Wide Human SNP
Array 6.0 and 729,779 SNPs passing QC were examined for
association with age at onset in BP. We analyzed the data
using polytomous logistic regression with three outcome
groups: early onset BP, late onset BP and controls. Our initial
focus was on the early vs. late onset BP comparison, which
yielded 375 loci at p

S14.4 GENOME-WIDE ASSOCIATION STUDIES
IDENTIFY A LOCUS ON CHROMOSOME 3P THAT
INFLUENCES BOTH BIPOLAR AND UNIPOLAR
DISORDER
F. McMahon* (1), N. Akula (1), T. Schulze (1), S.
Detera-Wadleigh (1), C. Steele (1), R. Breuer (2), J.
Strohmaier (2), J. Wendland (1), T. Mühleisen (3), W. Maier
(4), M. Nöthen (5), S. Cichon (5), M. Rietschel (2)
1. NIMH 2. Central Institute of Mental Health, Mannheim
3. Dept of Genomics, Life & Brain Center, Univ of Bonn 4.
Dept of Psychiatry, Univ of Bonn 5. Dept of Genomics, Life
& Brain Center, Univ of Bonn
* mcmahonf@mail.nih.gov
The major mood disorders, which include bipolar disorder and
major depressive disorder, are substantially heritable, but few
risk loci have been identified. We performed a meta-analysis
of five case-control samples assessed for the presence of a
major mood disorder, totaling 13,743 unique individuals
genotyped with approximately 500,000 to 1 million single
nucleotide polymorphism (SNP) markers on high-density
arrays. Imputation was used to compare SNPs across
platforms, and test statistics were weighted for sample size.
We found genome-wide significant evidence that SNPs in a
region of chromosome 3p21.1—containing the known genes
STAB1, NT5DC2, PBRM1, NEK4, SPCS1, GNL3,
GLT8D1,and ITIH1, 3, and 4—were associated with major
mood disorders. The SNP rs2251219 returned the smallest
meta-analysis p-value, 3.63 x 10-8, with a pooled odds ratio of
0.87. These results imply that one or more genes in 3p21.1
play an etiologic role in major mood disorders and suggest
that bipolar disorder and major depressive disorder share
genetic risk factors.
S14.5 GWAS AND META-ANALYSIS RESULTS FOR
PSYCHOSIS
N. Craddock* (1)
1. Cardiff University
* craddockn@cardiff.ac.uk
Even before the advent of GWAS, the pattern of molecular
genetic findings demonstrated evidence for an overlap in
genetic susceptibility across the traditional classification
categories - including association findings at DISC1 and
NRG1. Genome-wide association studies (GWAS) now
provide greater power to explore the relationship between
mood and psychotic illness. Several large-scale studies have
been undertaken, including those by our collaborators at the
Broad Institute of MIT and Harvard and the GAIN
Collaboration. Within the context of the Wellcome Trust Case
Control Consortium (WTCCC) we studied 2700
mood-psychosis cases and 3000 controls. In our data the
genome-wide significant associations at CACNA1C in bipolar
disorder and ZNF804A in schizophrenia show evidence for a
contribution to susceptibility across the traditional diagnostic
boundaries. Using both specific single risk alleles and also
composite “polygenic scores”, susceptibility to broadly
defined psychotic bipolar disorder does not appear to be
related in a simple way to susceptibility to schizophrenia.
However, there is evidence for the existence of some
relatively specific relationships between genotype and
psychopathology. For example, in our dataset variation at
GABAA receptor genes is associated with susceptibility to a
form of illness with mixed features of schizophrenia and
bipolar disorder. Recent genetic analyses of the WTCCC and
the larger collaborative datasets will be considered and the
implications for understanding psychotic bipolar disorder
discussed.

S14.6 CLINICAL HETEROGENEITY IN MOOD
DISORDERS
J. Smoller* (1)
1. Massachusetts General Hospital
* jsmoller@hms.harvard.edu
The modern distinctions between psychotic and mood
disorders date to Kraepelin’s foundational descriptions of
dementia praecox and manic depressive insanity more than a
century ago and Leonhard’s later division of bipolar and
unipolar disorders. These distinctions continue to be
fundamental organizing principles for psychiatric nosology,
but the diagnoses enumerated in DSM-IV are descriptive
syndromes that may not optimally capture the heritable basis
of psychiatric illness. Empirical evidence from clinical,
epidemiologic and genetic research has led to a growing
recognition that these diagnostic categories comprise
substantial heterogeneity. For example, several features of
mood disorders, including psychosis and early age at onset,
may index familial and genetic subtypes. The emergence of
large-scale, genomewide analyses have provided new
opportunities to dissect this heterogeneity. This presentation
will provide an overview of the evidence for clinical and
genetic heterogeneity in mood disorder syndromes and the
prospects for identifying genetic influences that transcend
diagnostic categories. The exploration of alternative
phenotype definitions present methodologic challenges but
may have important implications for enhancing the power of
genetic studies and informing an etiology-based nosology.
S15 THE WNT SIGNALING PATHWAY AND
SCHIZOPHRENIA
S15.1 GENETIC ASSOCIATION ANALYSIS OF THE
WNT SIGNALING PATHWAY IN SCHIZOPHRENIA
D. Collier* (1), P. Priotsi (1), The SGENE Consortium , S.
Lovestone (1)
1. Institute of Psychiatry, King's College, London
* david.collier@kcl.ac.uk
There is evidence from multiple sources that Wnt signalling is
involved in the aetiopathology of schizophrenia, suggesting
the hypothesis that genes in the wnt pathway are genetic
susceptibility factors for this illness. The accumulation of
genome wide association data in schizophrenia has made it
possible to test this hypothesis. In order to do so we performed
pathway association analysis using all known wnt signalling
genes their modifiers and targets in case-control GWAs data.
This includes the Dickkopf 4 (DKK4), which has previously
been found to show altered expression in schizophrenia brain
and to bind to neuregulin, and shows evidence of association
with schizophrenia.
S15.2 THE DISC1 PATHWAY MODULATES
EXPRESSION OF NEURODEVELOPMENTAL,
SYNAPTOGENIC AND SENSORY PERCEPTION
GENES
W. Hennah* (1), D. Porteous (2)
1. Institute for Molecular Medicine Finland FIMM, Nordic
EMBL Partnership for Molecular Medicine, Helsinki, Finland
2. Medical Genetics Section, University of Edinburgh, EH4
2XU, Edinburgh, UK
* william.hennah@thl.fi
Background: Genetic and biological evidence supports a role
for DISC1 across a spectrum of major mental illnesses,
including schizophrenia and bipolar disorder. There is
evidence for genetic interplay between variants in DISC1 and
in biologically interacting loci in psychiatric illness. DISC1
also associates with normal variance in behavioral and brain
imaging phenotypes. With recent studies demonstrating that
DISC1 binding partners also play a role in mental illness.
Methodology: Here, we analyze public domain datasets and
demonstrate correlations between variants in the DISC1
pathway genes and levels of gene expression. Genetic variants
of DISC1, NDE1, PDE4B and PDE4D regulate the expression
of cytoskeletal, synaptogenic, neurodevelopmental and
sensory perception proteins. Interestingly, these regulated
genes include existing targets for drug development in
depression and psychosis. Conclusions: Our systematic
analysis provides further evidence for the relevance of the
DISC1 pathway to major mental illness, identifies additional
potential targets for therapeutic intervention and establishes a
general strategy to mine public datasets for insights into
disease pathways.

S15.3 COPY NUMBER VARATION IN
SCHIZOPHRENIA
D. St. Clair (1)
1. Department of Mental Health, University of Aberdeen
A series of major articles have reported associations with
schizophrenia of copy number variants at 1q21, 15q11.2,
15q13.3, 16p11.2, 22q12, and Neurexin 1 loci. These are rare
high-penetrant mutations that increase risk not only of
schizophrenia but also of a range of other psychiatric disorders
including autism and mental retardation. Several copy number
variant loci include genes which impact on the wnt signalling
pathway. In some cases, the same phenotype can occur
irrespective of whether the copy number variant causes a
deletion or duplication. Although the loci identified so far
account for only a small proportion of cases, many more are
likely to be discovered over the next few years. A major focus
of research will be to identify the key, the genetic and
environmental determinants of schizophrenia risk in carriers of
these copy number variants, and to discover whether their
rates of mutation are unstable or fixed.
S15.4 HDAC-WNT/TCF SIGNALING CONTROLS
OLIGODENDROCYTE DIFFERENTIATION
Q. Lu* (1)
1. UT Southwestern Medical Center
* qrichard.lu@utsouthwestern.edu
Oligodendrocyte development is regulated by the interplay of
repressors and activators in a complex transcriptional network.
Here we report that two histone-modifying enzymes, HDAC1
and HDAC2, are required for oligodendrocyte formation.
Genetic deletion of both HDAC1 andHDAC2 in
oligodendrocyte lineage cells resulted in stabilization and
nuclear translocation of -catenin, which negatively regulates
oligodendrocyte development by repressing Olig2 expression.
We further identified an oligodendrocyte-restricted
transcription factor TCF7L2/TCF4 as a bipartite co-effector of
-catenin for regulating oligodendrocyte differentiation.
Targeted disruption of TCF7L2 in mice leads to severe defects
in oligodendrocyte maturation, while expression of its
dominant repressive form promotes precocious
oligodendrocyte specification in developing chick neural tube.
Transcriptional co-repressors HDAC1 and HDAC2 compete
with -catenin for TCF7L2 interaction to regulate downstream
genes involved in oligodendrocyte differentiation. Hence,
crosstalk between HDAC1/2 and the canonical Wnt signaling
pathway mediated by TCF7L2 serves as a regulatory
mechanism for oligodendrocyte differentiation.
S15.5 DISC1 REGULATES NEURAL PROGENITOR
PROLIFERATION VIA MODULATION OF
GSK3BETA/BETA-CATENIN SIGNALING
Y. Mao, X. Ge, C. Frank, J. Madison, A. Koehler, M. Doud,
C. Tassa, E. Berry, T. Soda, K. Singh, T. Biechele, T.
Petryshen , R. Moon , S. Haggarty , L. Tsai (1)
1. Howard Hughes Medical Institute; Picower Institute for
Learning and Memory, Department of Brain and Cognitive
Sciences, Massachusetts Institute of Technology, Cambridge,
MA 02139
* lhtsai@mit.edu
Schizophrenia is a severe brain illness that affects 0.5-1% of
the world population. While the etiology is poorly understood,
accumulating evidence suggest that neurodevelopmental
defects are involved. Recent studies have identified many risk
genes associated with schizophrenia. Among these genetic
factors, the (1; 11) (q42; q14.3) translocation allele of the
DISC1 gene closely segregates with the manifestation of
psychiatric disorders in a large Scottish pedigree. Functional
studies revealed that DISC1 is involved in neurite outgrowth,
neuronal migration, integration of newborn neurons, and
cAMP signaling. In addition, mouse models created by either
overexpressing a dominant negative form, deleting certain
exons, or ENU mutagenesis of DISC1 resulted in the
manifestation of schizophrenia- or depression-like behavioral
phenotypes in these mice. We found a novel role for DISC1 in
the proliferation of neural progenitors during embryonic and
adult neurogenesis. In searching for mechanisms to explain
how DISC1 regulates neurogenesis, we discovered that
downregulating levels of DISC1 abolished the ability of
Wnt3a to stimulate proliferation of neural progenitor cells,
suggesting DISC1 functions in the Wnt signaling pathway.
Moreover, the N-terminal region of DISC1 was found to
directly bind and inhibit GSK3b, thereby stabilizing b-catenin
levels. Most striking was the observation that the in vitro and
in vivo phenotypes due to DISC1 knockdown (both in the
embryonic or adult brain) could be rescued by either
overexpression of a degradation-resistant b-catenin, or by
pharmacological inhibition of GSK3b. This suggests the
cellular and behavioral results due to DISC1 knockdown can
be alleviated by hyperactivation of the canonical Wnt
signaling pathway. Together, these data strongly argue that
DISC1 is an important regulator of neural progenitor
proliferation that acts by positively modulating Wnt signaling
via inhibition of GSK3b.

S16 GENES, ENVIRONMENT AND
SUBSTANCE USE: EMERGING RESULTS
FROM SAGE
S16.1 ANALYSIS OF GWAS DATA FOR NICOTINE
DEPENDENCE: THE IMPORTANCE OF PHENOTYPE
DEFINITION AND CO-MORBID DIAGNOSES
J. Rice* (1), S. Saccone (1), N. Saccone (1), W. Howells (1),
K. Bucholz (1), D. Dick (2), K. Doheny (3), H. Edenberg (4),
V. Hesselbrock (5), J. Kramer (6), R. Krueger (1), S.
Kuperman (6), C. Laurie (7), R. Neuman (1), J. Nurnberger,
Jr. (4), B. Porjesz (8), E. Pugh (3), J. Tischfield (9), J. Wang
(1), L. Bierut (1), COGA, COGEND, GENEVA
1. Washington University, St. Louis, MO 2. Commonwealth
University, Richmond VA 3. CIDR Genotyping Lab and JHU
Center, Baltimore, MD 4. Indiana University, Indianapolis, IN
5. University of Connecticut, Farmington CT 6. University of
Iowa, Iowa City, IA 7. University of Washington, Seattle, WA
8. SUNY, Brooklyn, NY 9. Rutgers University, Piscataway,
NJ
* john@zork.wustl.edu
The SAGE addiction project, one of the GENEVA
(Gene-Environment Association) GWAS studies, consists of
data from three studies (alcohol dependence, cocaine
dependence and nicotine dependence). Cases had to have had
a diagnosis of alcohol dependence, and controls had neither a
diagnosis of alcohol dependence nor cocaine dependence.
Genotyping was performed on the Illumina 1M chip at CIDR
and data were cleaned following stringent GENEVA
standards. We analyzed the phenotype of nicotine dependence
using 1294 nicotine dependent cases and 2071 controls that
had smoked cigarettes but were not dependent. We first
considered issues related to ascertainment, co-morbidity and
phenotype definition, and then performed logistic regression
analysis for the phenotype of nicotine dependence. Covariates
consisted of gender, age (coded in four quartiles), ethnicity,
co-morbid alcohol dependence with and without cocaine
dependence, and SNP genotype coded additively with one
degree of freedom. We analyzed 1,341 SNPs present on the
Illumina chip in a set of 56 candidate genes previously
identified by a panel of experts and found significance in the
beta nicotinic receptor (CHRNB3) on chromosome 8 (p=2.4 x
10-8, OR = 1.54). These SNPs in CHRNB3 were the most
significant under GWAS analysis. Odds ratios were similar
for African Americans and European Americans as well as for
those with and without a co-morbid diagnosis. We emphasize
the importance of addressing co-morbidity in the analysis of
GWAS data for psychiatric phenotypes.
S16.2 A GENOMEWIDE ASSOCIATION STUDY
(GWAS) OF THE FIVE FACTOR MODEL (FFM) OF
PERSONALITY
R. Krueger* (1), A. Agrawal (1), J. Derringer (1), N. Wray
(2), R. Grucza (1), H. Edenberg (3), V. Hesselbrock (4), J.
Kramer (5), S. Kuperman (5), M. Lynskey (1), J. Nurnberger
Jr. (3), J. Tischfield (6), GENEVA, L. Bierut (1)
1. Washington University 2. Queensland Institute of Medical
Research 3. Indiana University 4. University of Connecticut 5.
University of Iowa 6. Rutgers University
* rkrueger@artsci.wustl.edu
Twin studies are consistent in attributing a substantial
proportion of the variation in human personality to genetic
factors. Nevertheless, the identities of the molecular genetic
variants that contribute to personality variation remain
elusive. We therefore pursued a Genomewide Association
Study (GWAS) of the Five Factor Model (FFM) of
personality, as assessed by the NEO-Five Factor Inventory
(NEO-FFI) in 2,223 unrelated research participants.
Genotyping was based on the 1M Illumina Platform,
with 948,142 single nucleotide polymorphisms (SNPs)
available for analysis after initial data cleaning. Three types
of results will be presented. First, we present standard GWAS
findings for each of the five personality traits (i.e., SNPs with
the lowest p-values).Second, we present p-values for SNPs
found to be associated with FFM traits in previous GWAS
research. Third, we present the results of a novel approach
to developing “genotypic scores.” Multiple SNPs found to be
predictive of personality variation in a development sample (a
random half of the participants) were used to develop five
scores characterizing genotypic standing on the five FFM
traits. Persons with higher genotypic scores have a greater
number of alleles predictive of higher FFM scores in the
development sample. The validity of these genotypic scores
for predicting personality was then ascertained in the
remaining half of the sample, i.e., in those participants not
used to develop the genotypic scores.

S16.3 GENOMEWIDE ASSOCIATION STUDIES OF
CANNABIS AND COCAINE DEPENDENCE
A. Agrawal* (1), M. Lynskey (2), A. Hinrichs (2), R. Grucza
(2), N. Saccone (2), S. Saccone (2), R. Krueger (3), R.
Neuman (2), W. Howells (2), S. Fisher (2), L. Fox (2), R.
Cloninger (2), D. Dick (4), K. Doheny (5), H. Edenberg (6),
A. Goate (2), V. Hesselbrock (7), E. Johnson (8), J. Kramer
(9), S. Kuperman (10), J. Nurnberger (6), E. Pugh (5), J.
Tischfield (11), COGA, COGEND, GENEVA, J. Rice (2), K.
Bucholz (2), L. Bierut (2)
1. Washington University School of Medicine Dept. of
Psychiatry, Email:arpana@wustl.edu 2. Washington Univ Sch
Med 3. Washington Univ St. Louis 4. Virginia
Commonwealth Univ 5. CIDR 6. Indiana Univ Sch Med 7.
Univ Connecticut Sch Med 8. RTI 9. Univ of Iowa College of
Med 10. Univ of Iowa Hospitals 11. Rutgers Univ
* arpana@wustl.edu
Cannabis is the most commonly used illicit psychoactive
substance in developed nations. After cannabis, cocaine
misuse contributed to 13% of admissions to treatment settings
in 2007. Prior twin studies have demonstrated considerable
genetic influences on both cannabis and cocaine dependence,
some of which are overlapping. Linkage and candidate gene
association studies have identified some variants associated
with dependence on either drug but results have been
equivocal. We conduct one of the first genomewide
association studies of DSM-IV cannabis dependence and
cocaine dependence using data from the Study of Addiction:
Genes and Environment (SAGE) which genotyped, using the
Illumina 1M, 4121 (54% female; 32.5% African-American)
individuals including 1944 cases (1965 exposed controls and
212 other/drug misuse) ascertained for alcohol dependence.
For our analyses, 753 and 1130 cases were available for
DSM-IV cannabis and cocaine dependence respectively. Our
top findings for cannabis dependence included polymorphisms
on chromosome 3 (p

S16.5 INTERPLAY OF GENETIC RISK FACTORS AND
PARENTS MONITORING IN RISK FOR NICOTINE
DEPENDENCE
L. Chen* (1), E. Johnson (2), N. Breslau (3), D. Hatsukami
(4), N. Saccone (5), R. Grucza (1), J. Wang (1), A. Hinrichs
(1), L. Fox (1), A. Goate (1), J. Rice (1), L. Bierut (1)
1. Washington University School of Medicine, Department of
Psychiatry 2. Research Triangle Institute International 3.
Michigan State University, Department of Epidemiology 4.
University of Minnesota, Department of Psychiatry 5.
Washington University School of Medicine, Department of
Genetics
* chenli@psychiatry.wustl.edu
Background: Several studies have found replicable
associations between nicotine dependence and specific
variants in the nicotinic receptor genes CHRNA5(rs16969968)
and CHRNA3(rs3743078). How these newly identified
genetic risks combine with known environmental risks is
unknown. This study examined whether the level of parent
monitoring during early adolescence modified the risk of
nicotine dependence associated with these genetic variants.
Methods: In a cross-sectional case control study of US-based
community sample of 2027 subjects, we use a systematic
series of regression models to examine the effect of parent
monitoring on risk associated with two distinct variants in the
nicotinic receptor genes CHRNA5(rs16969968) and
CHRNA3(rs3743078). Results: Low parent monitoring as well
as the previously identified genetic variants were associated
with an increased risk of nicotine dependence. An interaction
was found between the SNP(rs16969968) and parent
monitoring (p=0.034). The risk for nicotine dependence
increased significantly with the risk genotype of
SNP(rs16969968) when combined with lowest quartile parent
monitoring. In contrast, there was no evidence of an
interaction between SNP(rs3743078) and parent monitoring
(p=0.80). Conclusions: The genetic risk of nicotine dependent
associated with rs16969968 was modified by level of parent
monitoring, while the genetic risk associated with rs3743078
was not, suggesting that the increased risk due to some genes
may be mitigated by environmental factors such as parent
monitoring.
S16.6 GENETIC INFLUENCES ON SENSATION
SEEKING: MODERATION BY RELIGIOUS SERVICE
ATTENDANCE
J. Derringer* (1), R. Krueger (1, 2), D. Dick (3), R. Grucza
(2), A. Agrawal (2), L. Almasy (4), H. Edenberg (5), T.
Foroud (6), V. Hesselbrock (7), J. Kramer (8), S. Kuperman
(9), J. Nurnberger Jr. (10), B. Porjesz (11), M. Schuckit (12),
COGA, GENEVA, L. Bierut (2)
1. Department of Psychology, Washington University 2.
Department of Psychiatry, Washington University 3. Virginia
Institute for Psychiatric and Behavioral Genetics, Virginia
Commonwealth University 4. Genetics, Southwest Foundation
for Biomedical Research 5. Center for Medical Genomics,
Indiana University 6. Department of Medical and Molecular
Genetics, Indiana University 7. Department of Psychiatry,
University of Connecticut 8. Department of Psychiatry,
University of Iowa 9. Division of Child Psychiatry, University
of Iowa 10. Institute of Psychiatric Research, Indiana
University 11. Henri Begleiter Neurodynamics Laboratory,
SUNY Downstate Medical Center 12. Department of
Psychiatry, University of California – San Diego
* derringer@wustl.edu
The trait of sensation seeking (Zuckerman 1971) has been
associated with a range of psychiatric disorders, including
addiction, mania, and psychopathy. Twin studies indicate that
genetic factors account for significant variance in sensation
seeking, and sensation seeking has been associated with
biological markers, including MAO activity and sex hormone
levels (see Zuckerman, Buchsbaum, & Murphy 1980).
Religiosity moderates the influence of genetic factors on the
disinhibition scale of sensation seeking, where genetic factors
account for a greater proportion of variance in disinhibition for
individuals without a religious upbringing than for those
raised in religious environments (Boomsma et al. 1999). As
part of the Study of Addiction: Genes and Environment
(SAGE), we have been exploring the moderating role of
religious service attendance, one index of religiosity, on
genetic influences on substance dependence and related
phenotypes (Dick et al; accompanying presentation). We
examined moderation of genetic influences on sensation
seeking, a trait associated with substance dependence, by
religious service attendance. Our sample consisted of
644individuals from SAGE. More frequent religious service
attendance was associated with decreased overall sensation
seeking (r=-0.155, p

S16.7 INCORPORATING ENVIRONMENTAL
INFORMATION INTO GWAS: TESTING FOR
GENE-ENVIRONMENT INTERACTION AND
CORRELATION BETWEEN ALCOHOL
DEPENDENCE AND CHURCH ATTENDANCE
D. Dick* (1), J. Yan (2), F. Aliev (2), R. Krueger (3), A.
Agrawal (4), H. Edenberg (5), J. Kramer (6), M. Schuckit (7),
J. Tishcfield (8), B. Porjesz (9), V. Hesselbrock (10), S.
Kuperman (11), L. Almasy (12), J. Nurnberger (5), K. Kendler
(2), S. Aggen (2), L. Bierut (4), COGA, COGEND, GENEVA
1. Virginia Institute for Psychiatric and Behavioral Genetics
Virginia Commonwealth University Department of Psychiatry
2. Virginia Commonwealth University 3. Washington
University in St. Louis 4. Washington University School of
Medicine 5. Indiana University School of Medicine 6.
University of Iowa 7. University of California San Diego 8.
Rutgers University 9. State University of New York 10.
University of Connecticut School of Medicine 11. University
of Iowa Hospitals 12. Southwest Foundation for Medical
Research
* ddick@vcu.edu
Although most psychiatric disorders show considerable
evidence for genetic influence, the environment also plays an
important role. Furthermore, genetic and environmental
influences do not act in isolation, with twin studies providing
compelling evidence for both gene-environment interaction,
whereby the importance of genetic effects varies as a function
of the environment, and gene-environment correlation,
whereby the selection and experience of environmental events
is impacted by genetically-influenced characteristics. Despite
widespread recognition of the complex interplay between
genetic and environmental risk factors on psychiatric outcome,
most large-scale gene identification efforts to date have
largely ignored environmental effects. We have conducted a
series of analyses aimed at exploring the relationship between
alcohol dependence (AD) and church attendance. Religiosity
is known to play an important role in the development of AD,
with protective main effects (Kendler et al. 2003), and
moderating effects on genetic influences on alcohol use and
related phenotypes (Koopmans et al., 1999; Boomsma et al.,
1999). Analyses in the Virginia Adult Twin Study of
Psychiatric and Substance Use Disorders demonstrate genetic
covariance contributing to the correlation between church
attendance and AD. In the Study of Addiction: Genes and
Environment, a sample with GWAS data on 1944 AD cases
and 1965 controls, we find evidence for several loci that may
be involved in this gene-environment correlation between
religiosity and AD, as well as other loci where the association
with AD is moderated by religiosity. This study represents a
first step toward incorporating environmental information into
GWAS, using twin data to guide these efforts.

ORAL ABSTRACTS

O1 MOOD DISORDERS1
O1.1 SUPPORT FOR A BIPOLAR AFFECTIVE
DISORDER SUSCEPTIBILITY LOCUS ON
CHROMOSOME 12Q24.3
L. Foldager* (1), H. Buttenschøn (1), T. Flint (1), I. Olsen
(1), T. Deleuran (1), M. Nyegaard (2), M. Hansen (3), P.
Kallunki (4), K. Christensen (4), D. Blackwood (5), W. Muir
(5), S. Straarup (3), T. Als (3), M. Nordentoft (6), A. Børglum
(2), O. Mors (3)
1. Centre for Psychiatric Research, Aarhus University
Hospital, Risskov, Denmark 2. Institute of Human Genetics,
Aarhus University, Denmark 3. Centre for Psychiatric
Research, Aarhus University Hospital, Risskov, Denmark 4.
H. Lundbeck A/S, Valby, Denmark 5. Division of Psychiatry,
University of Edinburgh, UK 6. Psychiatric Centre Bispebjerg,
University of Copenhagen, Denmark
* Leslie.Foldager@ps.rm.dk
Linkage and association studies of bipolar affective disorder
(BP) point out chromosome 12q24 as a region of interest. In
order to investigate this region further, we conducted an
association study of 22 DNA markers within a 1.14 Mb region
in a Danish sample of 166 patients with BP and 311 control
individuals. Two hundred and four Danish patients with
schizophrenia (SZ) were also included in the study. We
observed highly significant allelic and genotypic association
between BP and two markers. The risk allele of both markers
considered separately conferred an odds ratio (OR) of two to
an individual carrying one risk allele and an OR of four for
individuals carrying both risk alleles assuming an additive
genetic model. These findings were supported by the
haplotype analysis. In addition we obtained a replication of
four markers associated with BP in a previous U.K. study.
The most significantly associated marker was also analyzed in
a Scottish case-control sample and was previously associated
with BP in the U.K. cohort. That particular marker was
strongly associated with BP in a meta-analysis of the Danish,
Scottish and U.K. sample (P=0.0003).The chromosome region
confined by our most distant markers is gene-poor and
harbours only a few predicted genes. The present study
implicates the Slynar locus. We confirmed one annotated
Slynar transcript and identified a novel transcript in human
brain cDNA. This study confirms 12q24.3 as a region of
functional importance in the pathogenesis of BP and
highlights the importance of focused genotyping.
O1.2 PER2 VARIATION IS ASSOCIATED WITH
DEPRESSION VULNERABILITY
C. Lavebratt (1), L. Sjöholm (1), T. Partonen (2), M.
Schalling (1), Y. Forsell (1)
1. Karolinska Institutet 2. Helsinki National Institute of Health
and Welfare
The circadian clock is driven by transcription-translation
feedback loops and regulates rhythms that approximate the
24-h day-night cycle or light-dark transitions. Disruptions of
the circadian rhythms are common in depressed patients,
expressed for example as sleep disturbances. Genetic
variations in core circadian genes may in part explain these
abnormalities. To investigate whether genetic variation in core
circadian genes associates with vulnerability to depression, we
genotyped 18 genes in a Swedish population based sample.
Genetic variations indicative of association with depression, or
with winter depression in our previous study, were tested for
association to depression in a second Swedish
depression-control sample set. PER2 genetic variation was
associated with depression vulnerability, and this genetic risk
did not seem to require exposure to potential sleep disturbance
factors such as negative life event or financial strain that are
known to increase the risk for depression. Polymorphisms
in the circadian genes NPAS2, ARNTL and RORA were also
suggested to contribute to depression vulnerability. The
findings we report for PER2, ARNTL and RORA are
supported by at least two of the three sample sets. In
conclusion, genetic variation in PER2 is associated with
depression vulnerability a Swedish population-based sample.
More studies are needed to determine if this is the case also
for NPAS2, ARNTL and RORA.

O1.3 GENOME WIDE ASSOCIATION SCAN OF
SUICIDALITY IN MAJOR DEPRESSION.
A. Schosser* (1), A. Butler (2), M. Ng (2), R. Uher (2), S.
Cohen-Woods (2), K. Pirlo (2), A. Elkin (2), N. Craddock (3),
M. Owen (2), K. Aitchison (2), A. Korszun (4), M. Barnes (5),
P. Muglia (5), M. Lathrop (6), S. Heath (6), G. Breen (2), A.
Farmer (2), I. Craig (2), P. McGuffin (2), C. Lewis (2)
1. MRC SGDP Centre, Institute of Psychiatry, King's College
London, UK; Dep. of Psychiatry and Psychotherapy, Medical
Univ. Vienna, Austria 2. MRC SGDP Centre, Institute of
Psychiatry, King's College London, UK 3. Department of
Psychological Medicine, Cardiff University, UK 4. Centre for
Psychiatry, Wolfson Institute of Preventive Medicine, Barts
and The London Medical School, Queen Mary University of
London, UK 5. GlaxoSmithKline Research & Development
6. Centre National de Genotypage, 91057 Evry, France
* alexandra.schosser@iop.kcl.ac.uk
Suicidal behaviour seems to cluster in families, and eritability
of completed suicide has been estimated as about 43%. Genes
predisposing to suicide may overlap with those predisposing
to affective disorder, since approximately half of those
committing suicide have a diagnosis of depression. We carried
out a genome-wide association (GWA) study in 2947 subjects
with DSM-IV and/or ICD-10 major depression, derived from
three studies: DeCC (Depression Case Control, N=1145),
GENDEP (Genome-based Therapeutic Drugs for Depression,
N=729), DeNt (Depression Network, N=918), and a sample
collected by GSK (Glaxo Smith Kline, N=155). Depression
and suicidality were assessed using SCAN, and a new variable
summarising suicidal behaviour (SSB), composed of SCAN
items 6.011 (suicide or self-harm, score 0-4) and 6.012 edium
vitae, score 0-3), was created. All subjects therefore had a
score between 0 and 7 for the worst and 2nd worst episode, or
current episode in GENDEP. This quantitative trait SSB was
correlated with number of episodes of depression and with
early age of onset, but not gender. We performed enome-wide
analysis of the quantitative SSB phenotype, and a discrete trait
(SSB6, with N=275 cases), correcting for the
Europe-wide ascertainment of cases. Four SNPs attained
p-values of

O1.5 SYSTEMATIC ANALYSIS OF CIRCADIAN
GENES IN A POPULATION-BASED SAMPLE
REVEALS ASSOCIATION OF TIMELESS TO
DEPRESSION AND SLEEP DISTURBANCE
S. Utge (1), P. Soronen (1), A. Loukola (1), E. Kronholm (2),
V. Leppä (3), S. Pirkola (4), T. Porkka-Heiskanen (5), T.
Partonen (6), T. Paunio* (7)
1. Public Health Genomics Unit, National Institute for Health
and Welfare, Helsinki 2. Department of Health and Functional
Capacity, Laboratory for Population Research 3. Public Health
Genomics Unit, National Institute for Health and Welfare,
Helsinki and Institute for Molecular Medicine Finland FIMM,
University of Helsinki 4. Department of Psychiatry, Helsinki
University Central Hospital, Helsinki
5. Department of Physiology, University of Helsinki, Helsinki,
Finland 6. Department of Mental Health and Substance Abuse
Services, National Institute for Health and Welfare, Helsinki
7. Public Health Genomics Unit, National Institute for Health
and Welfare, Helsinki and Department of Psychiatry, Helsinki
University Central Hospital, Helsinki
* tiina.paunio@thl.fi
Background: Circadian rhythm abnormalities and disturbed
sleep is a prevalent sign of depression. We have recently
showed that poor sleep quality is a risk factor for incidence of
depressed mood (Paunio et al. 2009) and that there are
sex-dependent and symptom specific differences in the genetic
back ground of depression at population level (Utge et al. in
press). We hypothesized that some of the genetic variants
from the circadian system might be a contributing causal
factor for depression with signs for disturbed sleep, early
morning awakenings, or day-time fatigue. Materials and
methods: We tested this hypothesis in a population-based
sample of Health 2000 from Finland, including 384 depressed
individuals and 1270 controls, all with detailed information on
sleep and day-time vigilance, and analyzed this set of
individuals against 113 single nucleotide variants from 18
genes of the circadian system. Association of genetic variants
to depression with signs of disturbed sleep was investigated
using allelic permutation tests, followed by haplotype
analyses, and finally gene-gene interaction analyses for the
most significant findings. Results: We found significant
association of variants from TIMELESS to depression with
fatigue (P = 0.0001 for single variant and P = 0.000008 for a
haplotype across the gene) in females and suggestive
association to depression with early morning awakenings (P =
0.0009 for single variant and P = 0.0001 for 2-SNP haplotype)
in males. There was some evidence of interaction between
TIMELESS and other circadian genes both in females and
males. Conclusions: The current findings support the
involvement of circadian system in the regulation of
depression and sleep in a sex dependent manner.
References: Paunio T, Korhonen T, Hublin C, Partinen M,
Kivimäki M, Koskenvuo M, Kaprio J. (2009) Longitudinal
study on causality and genetic risk factors for the association
between poor sleep and life dissatisfaction in a nationwide
cohort of twins. Am J Epidemiol. 169(2):206-13; Utge S,
Soronen P, Partonen T, Loukola A, Kronholm E, Pirkola S,
Nyman E, Porkka-Heiskanen T, Paunio T. A population-based
association study of candidate genes for depression and sleep
disturbance. Am J Med Genet B Neuropsychiatr Genet. in
press Acknowledgments: Funding from STREP, Call:
FP6-2004-Lifescihealth-5 ; Enough sleep (to T. Paunio)
O1.6 PI3K/AKT SIGNALING IN DOPAMINERGIC
ACTION
K. Celestrin (1), K. Carr (1), T. Franke (1)
1. NYU School of Medicine
One biochemical change acquired following induction of
depression-like behavior and exposure to drugs of abuse is
altered phosphorylation of the Aktserine-threonine kinase in
dopaminergic neurons. Here, we have asked if altered Akt
signal transduction affects behavioral responses in
experimental paradigms related to mesolimbic/nigrostriatal
dopamine signaling. To answer the question, we have used
Akt1-mutant mice. Akt1 is a major isoform of the Akt kinase
family and expressed at high levels in dopaminergic neurons.
Loss-of-function Akt1-mutantmice exhibited a phenotype in
the learned helplessness paradigm. In this experimental model
for acquired behavioral depression, the exposure to
inescapable electric foot shocks (IES) disrupts the escape to
subsequent noxious stimuli. While no significant differences
were observed between sham-treated control mice depending
on genotypes, IE-shocked Akt1-mutant mice showed
increased latencies of crossing and a higher number of escape
failures when compared to IES-treated wild-type mice. In
further support of the importance of intact Akt signaling in
dopaminergic signaling, Akt1-mutantmice displayed an
enhanced response to acute cocaine and a diminished
sensitization effect to chronic cocaine exposure. Western
blotting and immunohistochemical analyses after IES training
revealed genotype-dependent changes in Akt phosphorylation
and regulation of its downstream substrates of Akt and its
substrates following IES training. These biochemical state
changes phenocopied differences in behavioral outputs when
comparing wild-type and Akt1-mutantmice. This work is
supported in part by the National Science Foundation (NSF
award IOS-0757780) and the G. Harold & Leila Y. Mathers
Foundation (toTFF), and by the National Institute on Drug
Addiction/NIH (DA003956) (to KDC). Dr. Franke is
supported in part by a 2008 NARSAD Independent
Investigator Award.

O1.7 TPH2 RISK HAPLOTYPE ASSOCIATED WITH
IMPULSIVE AGGRESSION IN BORDERLINE
PERSONALITY DISORDER
L. Siever* (1), A. New (1), M. Perez-Rodriguez (2), S.
Weinstein (2), L. Bevilacqua (3), Q. Yuan (3), Z. Zhou (3), C.
Hodgkinson (3), M. Goodman (1), H. Koenigsberg (1), D.
Goldman (3)
1. Mount Sinai School of Medicine/Bronx VA Medical Center
2. Mount Sinai School of Medicine 3. NIAAA/NIH
* Larry.Siever@va.gov
The serotonin system has been implicated in the regulation of
impulsive aggression and in the pathogenesis of borderline
personality disorder on the basis of neuropharmacologic,
neuroimaging, and treatment studies. Reduced serotonergic
activity is associated with reduced prefrontal control of the
emergence of aggression upon emotional provocation.
Responses to fenfluramine agent and imaging of serotonin
synthesis with methyl-L-tryptophan trapping suggest reduced
presynaptic serotonergic activity. TPH2 is the rate limiting
step for serotonin synthesis in the brain and this study was
designed to evaluate the genetics of TPH2 in relation to
impulsive aggression in borderline personality and a cohort of
251 personality disorder patients and 103 healthy controls.
All subjects were free of medication, screened for medical
problems, and met criteria for a personality disorder and were
evaluated diagnostically and using a composite measure of
aggression based on the Buss Perry Aggression Inventory.
123 Caucasian subjects were evaluated for a risk haplotype
associated with reduced serotonergic activity and suicide in a
Finnish cohort (Zhou et al, 2005). In our study subjects
carrying the risk haplotype demonstrated higher aggression
scores and were more likely to be diagnosed with borderline
personality disorder (p

O2.2 MOLECULAR NETWORKS OF LITHIUM
RESPONSE: CONVERGENCE ACROSS PHYLOGENY
A. Gupta (1), T. Schulze (2), N. Akula (1), F. McMahon (1),
S. Detera-Wadleigh (1)
1. NIMH 2. NIMH PI3K/AKT Signaling In Dopaminergic
Action
How lithium elicits mood stabilization in bipolar disorder
patients has not been fully explained. Perturbations by lithium
in key components of the phosphoinositide and Wnt
signaling pathways have been demonstrated consistently,
recommending their prominent role in lithium response. To
evaluate the global effect of lithium, we assembled expression
studies performed in various organisms and identified
differentially expressed genes and proteins. We sought to
capture, through pathway analysis, the biological relationships
of these genetic factors. This generated a molecular network
that may unify the disparate mechanisms recruited by the drug
and exposes potential markers for lithium response. Genes up-
and down-regulated by lithium were initially identified from
>20 gene-based and 5 protein-based studies, with a focus on
large microarray studies. Homologs significantly regulated in
the same direction across two or more species/studies were
given preference and fed into the pathway analysis programs
Ingenuity and Cytoscape. Enzymes classically shown to alter
lithium response were also included. Networks resulting from
both were compared for overlaps and hubs of importance
verified. Two pathway analysis tools were trained on 19
lithium-responsive genes and proteins/enzymes. Major gene
hubs centered at AKT1, BCL2, CALM, EZR and GSK3B
and minor ones localized at ATF4, PTGS2, BDNF, CRYAB,
SYN1. Where these cores converged could be considered key
features of the network. Although multiple genes populate the
networks, coalescence into a more unified molecular
repertoire may underlie the overall effect of
lithium. Conceivably, some genes may be used as new drug
targets and diagnostic tools as well.
O2.3 BEHAVIORAL ANALYSES OF TRANSGENIC
MICE HARBORING BIPOLAR DISORDER
CANDIDATE GENES, IMPA1 AND IMPA2
T. Yoshikawa* (1), T. Ohnishi (1)
1. RIKEN Brain Science Institute
* takeo@brain.riken.jp
IMPase (myo-inositol monophosphatase) generates free
inositol from inositol monophosphate. The inositol depletion
hypothesis proposes the inhibition of IMPase by lithium, a
mood stabilizer, as a mechanism of lithium’s efficacy. This
hypothesis predicts that the upregulation of this biochemical
pathway may underlie the pathophysiology of bipolar
disorder. In favor of this idea, we have recently shown that
IMPA2 encoding IMPase is a candidate susceptibility gene for
bipolar disorder and that the risk-conferring single nucleotide
polymorphisms (SNPs) enhance the promoter activity of
IMPA2. Furthermore, some studies have suggested an
increase in the myo-inositol content in the brains of
bipolar patients. However, it is yet unknown whether such
upregulation has a biological role in bipolar disorder. To
address this issue, we generated Tg (transgenic) mice for the
two human IMPase genes (IMPA1 and IMPA2) under the
control of brain-specific promoters, and examined them using
multiple behavioral test batteries. The Tg mice behaved
normally except for subtle changes in some paradigms
under durg-naïve conditions, and did not exhibit signs for
manic change when an antidepressant amitriptyline was
chronically administrated. Interestingly, the male Tg mice for
IMPA2 exhibited a lithium-resistant phenotype in the forced
swim test. The current study did not support a substantial
role of the upregulation of IMPase in the pathogenesis of
bipolar disorder, at least from animal experiments, although
the lithium-insensitivity trait seen in IMPA2 Tg mice might
represent some aspect relevant to the inositol depletion
hypothesis.

O2.4 CANDIDATE GENE PHARMACOGENETICS
STUDY OF MGLU 2/3 AGONIST LY2140023
A. Downing (1), W. Liu (1), L. Shen (1), L. Munsie (1), P.
Chen (1), B. Han (1), J. Brandt (1), R. Njau (1), B. Kinon (1),
L. Nisenbaum (1)
1. Eli Lilly and Company
LY2140023 is the oral prodrug of LY404039, a selective
agonist for metabotropic-glutamate 2/3 (mGlu) receptors.
LY2140023 is currently under development for the treatment
of schizophrenia and has the potential to introduce a novel
mechanism of action for antipsychotics. The primary goal of
the pharmacogenetics effort is to identify genetic markers that
are predictive of patients’ response to LY2140023 and could
be used to target specific subpopulations for treatment.
Genetic variants in eight candidate genes related to the
mechanism of action of LY2140023 or the atypical
antipsychotic olanzapine were investigated in DNA samples
collected as part of the Phase II proof of concept trial,
H8Y-MC-HBBD. Primary statistical analysis was conducted
on 193 Caucasian patients treated with either placebo,
LY2140023 or olanzapine using an ANCOVA model
assuming LOCF and additive inheritance. Associations
between LY2140023 response and genotypes were identified
for SNPs within the HTR2A and NRG1 genes. Three SNPs (1
in NRG1, 2 in HTR2A) were statistically significantly
associated with LY2140023 response at 28 days as measured
by Positive and Negative Syndrome scale (PANSS) Total
change from baseline. All three SNPs had unadjusted p-values
less than 0.001 (FDR=0.114) at 28 days. These SNPs were
investigated in a second cohort collected from trial
H8Y-MC-HBBI, which had an inconclusive primary clinical
endpoint. While the genetic results did not reach statistical
significance in HBBI, the HTR2A minor homozygous group
showed the greatest treatment response in both HBBD and
HBBI. In conclusion, these data suggest that a genetic
association may impact response to LY2140023 treatment.
O2.5 CONVERGENT ANIMAL AND HUMAN
EVIDENCE FOR A ROLE OF PPM1A GENE IN
RESPONSE TO ANTIDEPRESSANTS
K. Malki* (1), R. Uher (1), E. Binder (1), J. Payo-Cano (1),
C. Lewis (1), J. Rietschel (1), W. Maier (1), O. Mors (1), J.
Hauser (1), N. Henigsberg (1), B. Jerman (1), D. Souery (1),
A. Placentino (1), K. Aitchison (1), A. Farmer (1), I. Craig (1),
L. Schalkwyk (1)
1. IOP
* karim.malki@iop.kcl.ac.uk
Anti-depressant drugs are used as first line treatment in
depression but response has been shown to be highly
heterogeneous with drugs often failing to have the desired
therapeutic effect. We report on an integrative analysis from
the Genome-based Therapeutic Drugs for Depression
(GENDEP) study using gene expression from mice to inform
prioritisation in human pharmacogenetic GWAS. The same
two antidepressants were used in mice and humans:
escitalopram (a serotonin-reuptake inhibitor) and nortriptyline
(a norepinephrine-reuptake inhibitor). The animal study used
four inbred strains of mice (129S1/SvlmJ, C57LB/6J, DBA/2J
and FVB/NJ), and two stress protocols (maternal separation
and chronic mild stress). Hippocampus mRNA data was
measured in 144 animals using the Affymetrix 430 chip.
Behavioural data informed gene-expression analysis looking
for Strain(G)xDrug(E) interactions. Twenty-six genes were
identified as being differentially expressed according to strain
and drug, including the phosphatase 1A gene (Ppm1a)
differentially expressed with nortriptyline vs. saline. Single
nucleotide polymorphisms tagging common sequence
variation in human homologues of these genes were tested for
association with response to antidepressants in 706
participants of the GENDEP human pharmacogenetic study,
treated with escitalopram or nortriptyline for 12 weeks, with
available high-quality Illumina 610quad chip genotyping.
Several polymorphisms in the protein phosphatase 1A gene
(PPM1A) were significantly associated with response to
nortriptyline in humans after correction for multiple testing.
PPM1 encodes a phosphatase involved in MAP kinase
signalling and cell stress response. The convergent evidence
from mice and humans points to a role of the PPM1A in
response to noradrenergic but not serotonergic antidepressants.

O2.6 INDIVIDUALIZED ANTIPSYCHOTIC THERAPY
FOR SCHIZOPHRENIA
K. Aberg* (1), J. McClay (1), D. Adkins (1), J. Bukszar (1),
P. Jia (2), Z. Zhao (2), V. Vladimirov (3), J. Lieberman (4), P.
Beardsley (5), P. Sullivan (6), E. van den Oord (7)
1. Center for Biomarker Research and Personalized Medicine,
Virginia Commonwealth University 2. Department of
Biomedical Informatics, Vanderbilt University Medical Center
3. Virginia Institute for Psychiatric and Behavioral Genetics,
Virginia Commonwealth University 4. Department of
Psychiatry, Columbia University 5. Department of
Pharmacology and Toxicology, Virginia Commonwealth
University 6. Department of Genetics, University of North
Carolina at Chapel Hill 7. Center for Biomarker Research and
Personalized Medicine, Virginia Commonwealth University;
Virginia Institute for Psychiatric and Behavioral Genetics,
Virginia Commonwealth University
* kaaberg@vcu.edu
Understanding individual variation causing differences in
efficacy and development of adverse effects, as a response to
antipsychotic therapy is essential to optimize and individualize
the treatment for schizophrenia. Genetic variations may
potentially affect the response to antipsychotic treatment.
We are conducting a series of genomewide association studies
(GWAS) in the Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE) for a wide variety of efficacy (e.g.
disease symptoms, neurocognition) and toxicity (e.g. QT
prolongation, movement and metabolic side effects) measures.
To study these measures, we developed a systematic method
to estimate treatment effects in CATIE that combines
information from all assessments in an empirical fashion.
After quality control, 492K successfully genotyped SNPs were
available for 738 schizophrenia patients. Several signals
reached genomewide significance at our pre-specified
threshold ensuring that no more than 10% of our significant
findings are expected to be false discoveries. A SNP in MEIS2
mediated the effect of risperidone on hip and waist
circumference and showed secondary associations with BMI,
and blood pressure. Another SNP, located in SLC22A23,
mediated the effect of quetiapine on QT prolongation. Many
other signals were found for genes that are good candidates for
further studies. We are developing a user-friendly databases to
store all GWAS results. This database allow other researchers
to design replication studies, search the CATIE results to
confirm their findings, perform cross-outcome analyses, and
combine new data with the CATIE GWAS results.
Furthermore, we are currently developing methods to
incorporate pathway information in the analyses, which will
improve the statistical power.
O3 ANXIETY
O3.1 THE SYMPTOMATIC PROFILE OF PANIC
DISORDER IS SHAPED BY THE 5-HTTLPR
POLYMORPHISM
T. Lonsdorf (1), M. Schalling* (1), C. Ruck (1), J. Bergstrom
(1), G. Andersson (2), A. Ohman (1), N. Lindefors (1)
1. Karolinska Institutet 2. Uppsala University
* martin.schalling@ki.se
The short allele of a functional polymorphism (5-HTTLPR) in
the serotonin transporter is associated with reduced serotonin
transporter (5-HTT) expression and also with neuroticism,
amygdalare activity and facilitated fear conditioning. Thus the
5-HTTLPR is a candidate variant for panic disorder. However,
case-control studies have consistently failed to show an
association between 5-HTTLPR and panic disorder. As
psychiatric disorders are broadly defined phenotypes merging
different symptoms to syndromes, they may not be very well
suited for genetic association studies. An alternative approach
is to measure symptoms along continuous psychological
dimensions which may more appropriately reflect their
biological underpinnings and may reveal subpopulations
within clinical diagnostic groups. We recorded the
symptomatic profile in 73 mainly Caucasian panic disorder
patients using observer-rated instruments (Panic Disorder
Severity Scale, PDSS; Montgomery-Åsberg Depression
Rating Scale, MADRS) prior to treatment, after10-weeks of
psychological treatment and six months after treatment. We
observed a strong and time-stable association between bi-and
triallelic 5-HTTLPR polymorphisms and the symptomatic
profile. Carriers of the 5-HTTLPR s-allele suffered from more
severe panic and depressive symptoms as compared to those
homozygous forthe l-allele. Our data highlight the importance
of defining appropriate phenotypes for psychiatric genetic
studies and demonstrate that the 5-HTTLPR genotype may be
related to the symptomatic profile rather than to the
vulnerability to develop panic disorder.

O3.2 POLYMORPHISMS IN THE GENE ENCODING
THE NEUROPEPTIDE GALANIN ARE ASSOCIATED
WITH HPA-AXIS DYSREGULATION AND
SYMPTOME SEVERITY IN MAJOR-DEPRESSIVE-
AND ANXIETY-DISORDER PATIENTS.
P. Unschuld* (1), M. Ising (1), D. Roeske (1), A. Erhardt (1),
M. Specht (1), S. Ripke (1), M. Uhr (1), S. Kloiber (1), B.
Müller-Myhsok (1), F. Holsboer (1), E. Binder (1)
1. Max Planck Institute of Psychiatry, Kraepelinstr. 2-10,
80804 München, Germany
* unschuld@mpipsykl.mpg.de
Galanin (GAL) is an estrogen inducible neuropeptide, highly
expressed in brain-regions processing mood and behavior.
GAL possibly has a direct modulatory effect on
hypothalamic-pituitary-adrenal axis (HPA) regulation, as
recent pharmacological and genetic studies indicate a
significant role of GAL in stress-related disorders.
By using a tag SNP approach covering the GAL-gene, we
expanded an earlier finding of a genetic association with
panic-disorder in female subjects to a larger sample of 268
outpatients with anxiety disorders (AD) and 541 inpatients
with major depressive disorder (MDD). As intermediate
phenotype for treatment response, HPA-axis dysregulation
using the combined dexamethasone suppression / CRH
stimulation test both at admission and discharge was evaluated
in 298 MDD-inpatients. To test for case-control associations,
a healthy control sample (n=541) was used. Genotyping
revealed high LD in the promotor area of the GAL-gene,
including predescribed estrogen binding element sites. We
found associations of the rare allele of rs948854 in female
AD-patients with more severe anxious pathology and in
premenopausal MDD-patients with higher HPA-axis activity
at admission, more severe anxious pathology at discharge and
non-remission. No significant case-control associations could
be observed. The here presented data suggest a gender-specific
role of GAL SNPs in liability for anxious and depressive
disorders, characterized by a particularly dysregulated
HPA-axis.
O3.3 VARIANTS IN SLITRK1 ARE ASSOCIATED
WITH THE OBSESSIVE-COMPULSIVE DISORDER
SPECTRUM
U. Ozomaro* (1), R. Moessner (2), M. Cuccaro (1), M.
Pericak-Vance (1), M. Wagner (2), G. Feng (3), S. Zuchner
(1)
1. Miami Institute for Human Genomics, University of Miami,
Miami, USA 2. Psychiatrische Klinik der Universitaet Bonn,
Bonn, Germany 3. Department of Neurobiology, Duke
University Medical Center, Durham, USA
*uozomaro@med.miami.edu
Obsessive-Compulsive Disorder (OCD) and the spectrum of
closely related disorders are characterized by persistent
intrusive thoughts (obsessions), repetitive actions
(compulsions), and excessive anxiety. Although heritability
studies in OCD have shown an increased risk for first degree
relatives, and twin studies revealed higher concordance
amongst monozygotic twins (compared to dizygotic twins),
the identification of the underlying risk-conferring genetic
variation by means of classic genetic association studies has
proven to be difficult. Recently, the possibility of a larger
contribution of rare genetic variants to the risk of psychiatric
disorder has been suggested by several successful studies. In
accordance with this hypothesis we applied a rare variant
association study design to explore SLITRK1, a gene
previously linked to disorders of the OCD spectrum. We
directly resequenced SLITRK1 in 279 OCD spectrum cases
and in 185 psychiatric controls. We identified two novel
nonsynonymous variants in five cases, N400I and T418S. The
N400I variant was found in one case, while the T418S change
was identified in four cases. Neither variant, nor any other
nonsynonymous changes were detected in the controls. In a
previous study, we identified two rare variants in SLITRK1,
R584K and S593G, whose sequence changes were
significantly associated with trichotillomania, an OCD
spectrum disorder. Taking into consideration the combined
mutation load of our two studies, OCD spectrum cases are
significantly associated with variants in SLITRK1 (complete
gene sequencing; p=0.043, Fisher’s exact test). SLITRK1
codes for a neurite modulating protein and is found in the
striatum. Additional support for a role of SLITRK1 in OCD
spectrum disorders comes from a recent SLITRK1 knockout
mouse characterized by anxiety and mirroring aspects of the
human disorder. We are currently performing functional
in-vitro studies to further clarify the molecular consequences
of these variants.

O3.4 ACCELERATED TELOMERE SHORTENING IN
A POPULATION-BASED NESTED CASE-CONTROL
STUDY OF ANXIETY DISORDER PATIENTS
L. Kananen (1), I. Surakka (2), S. Pirkola (3), J. Suvisaari (4),
J. Lönnqvist (4), L. Peltonen (5), S. Ripatti (2), I. Hovatta*
(6)
1. Mol Neurol Res Program, Univ Helsinki, Finland 2. Public
Health Genomics Unit, Natl Inst for Health and Welfare;
FIMM, Inst for Mol Med Finland, Univ Helsinki, Finland 3.
Dept of Psychiatry, Helsinki University Central Hospital
Finland 4. Mental Health and Substance Abuse Services, Natl
Inst for Health and Welfare, Helsinki, Finland 5. FIMM, Inst
of Mol Med Finland, Univ Helsinki; Wellcome Trust Sanger
Inst, Hinxton, UK 6. Mol Neurol Res Program, Univ Helsinki;
Mental Health and Substance Abuse Services, Natl Inst for
Health and Welfare; Dept of Med Genet, Univ Helsinki,
Finland
* iiris.hovatta@helsinki.fi
Accelerated telomere shortening has been previously
associated to self-perceived stress and psychiatric disorders,
including schizophrenia and mood disorders. We hypothesized
that accelerated telomere shortening might be involved in the
etiology of anxiety disorders, in which stress and stressful life
events are major environmental predisposing factors. We set
out to test this hypothesis in a randomly selected
population-based Health 2000 cohort with 974 samples
including 321 anxiety disorder patients and 653 matched
controls aged 30-87 years, who all underwent Composite
International Diagnostic Interview. Relative telomere length of
peripheral blood cells was measured by quantitative real-time
PCR. Anxiety disorder patients in the older age group (48-87
years) exhibited significantly shorter telomeres than healthy
controls. The association was highly stable and robust across
adjustments for previously associated factors and potential
confounders. In the whole sample and the younger age group
(30-47 years), shorter telomere length was associated with
greater number of childhood adverse life events, both in the
anxiety disorder cases and controls. Childhood chronic illness
was the most significantly associated single event affecting
telomere length at the adult age. Self-reported current
psychological distress, as measured by GHQ-12, did not have
an effect on the telomere length. Our results suggest that
accelerated telomere shortening in anxiety disorder patients is
likely due to a long-term stress related to anxiety disorders.
This finding strengthens the hypothesis that oxidative stress,
which is known to affect telomere length, is involved in the
pathogenesis of anxiety disorders.
O3.5 PRIORITIZATION AND ASSOCIATION
ANALYSIS OF MURINE-DERIVED CANDIDATE
GENES IN ANXIETY-SPECTRUM DISORDERS
J. Hettema (1), B. Webb (1), A. Guo (2), Z. Zhao (2), B.
Maher (1), X. Chen (1), S. An (1), C. Sun (1), K. Kendler (1),
P. Kuo (3), J. Flint (4), E. van den Oord (1)
1. Virginia Commonwealth University 2. Vanderbilt
University 3. National Taiwan University 4. Oxford
University
* jhettema@vcu.edu
Introduction: Anxiety disorders are common psychiatric
conditions that are highly comorbid with each other and
related phenotypes such as depression and personality,
possibly due to a shared genetic basis. Fear-related behaviors
in mice have long been investigated as potential models of
anxiety-spectrum disorders, making integration of information
from both murine and human genetic data a powerful strategy
for identifying potential susceptibility genes for these
conditions. Methods: A genome-wide association analysis
(GWAS) of fear-related behaviours in heterogeneous
stock mice identified a preliminary list of 54 novel candidate
genes. We ranked these according to three complementary
sources of anxiety-related genetic data: (1) human linkage
scans, (2) a human GWAS study, and (3) linkage and
knock-out studies in mice. We genotyped tagging SNPs
covering the nine top-ranked genic regions in a two-stage
association study of subjects genetically informative for
anxiety-spectrum disorders. Results: Stage 1 screening
identified SNPs in several of the regions that demonstrated
suggestive association that were carried forward for
genotyping in stage 2. While most of these did not retain their
association in stage 2, multiple SNPs and related haplotypes in
the PPARGC1A gene did. Conclusions: Integration of genetic
data across human and murine studies suggests PPARGC1A
as a potential susceptibility gene for anxiety-spectrum
disorders.

O4 ADHD
O4.1 HAPLOTYPE SEGREGATION IN MULTIPLEX
ADHD FAMILIES AT DIFFERENT CHROMOSOMAL
LOCI
M. Lin* (1), T. Nguyen (2), C. Freitag (3), H. Palmason (1),
C. Seitz (4), T. Renner (5), M. Romanos (5), S. Walitza (5), C.
Jacob (6), K. Lesch (6), J. Meyer (1)
1. Institute of Psychobiology, Department of Neurobehavioral
Genetics, Trier, Germany 2. Institute of Medical Biometry and
Epidemiology, Philipps-University, Marburg, Germany 3.
Goethe-University Frankfurt am Main, Department of Child
and Adolescent Psychiatry, Frankfurt, Germany 4. Saarland
University Hospital, Department of Child and Adolescent
Psychiatry, Homburg, Germany 5. Universityof Wuerzburg,
Department of Child and Adolescent Psychiatry and
Psychotherapy, Wuerzburg, Germany Wuerzburg, Germany 6.
University of Wuerzburg, Department of Psychiatry and
Psychotherapy, Wuerzburg, Germany
* s1kalinn@uni-trier.de
Attention-deficit hyperactivity disorder (ADHD) is a
neuropsychiatric disorder characterized by symptoms of
inattention, hyperactivity and increased impulsiveness.
Despite many studies over the last decades, the etiology of
ADHD remains unknown. Eight large ADHD-affected
families were recruited in a multicenter collaboration study
conducted by three clinical units of child and adult psychiatry
(Universities of Trier, Homburg/Saar, and Wuerzburg). They
comprised of 191 individuals, of which 95 were afflicted with
ADHD. Fine-mapping with microsatellite markers of the
significant loci reported in our recent paper (Romanos et al,
2008) of a genome-wide linkage study of the eight large
families was carried out. Using genetic data derived from
related individuals within each of the large families, an
attempt is made to identify predisposing chromosomal regions
in these families by verifying which of these significant
regions actually segregate among the ADHD-affected
individuals in the pedigrees. Several of the large ADHD
families show evidence of haplotype segregation at 1q25
(HLOD = 2.99, p = 0.00021, alpha = 0), 9q22 (LOD = 2.61, p
= 0.00053), 12p13 (LOD = 3.07, p = 0.00017), p = 0.0000065)
and 18q11 (LOD = 2.90, p = 0.00026). Evidence of multiple
segregating loci suggests genetic heterogeneity. To better
discern the complexly inherited trait of ADHD, we will assess
the segregating loci in these families in order to identify
plausible candidate genes and variants contributing to the
disorder. Further studies on these segregating regio regions of
chromosomes will be executed with next-generation
sequencing techniques.
O4.2 A NEURODEVELOPMENTAL PATHWAY FOR
ATTENTION DEFICIT HYPERACTIVITY DISORDER
(ADHD) : INTEGRATING THE GENOME-WIDE
ASSOCIATION FINDINGS
G. Poelmans (1), D. Pauls (2), J. Buitelaar (1), B. Franke* (3)
1. Department of Psychiatry, Donders Institute for Brain,
Cognition and Behaviour, Radboud University Nijmegen
Medical Centre, Nijmegen, The Netherlands 2. Psychiatric and
Neurodevelopmental Genetics Unit, Center for Human
Genetic Research, Massachusetts General Hospital, Harvard
Medical School, Boston, USA 3. Department of Psychiatry,
Donders Institute for Brain, Cognition and Behaviour,
Radboud University Nijmegen Medical Centre, Nijmegen,
The Netherlands and Department of Human Genetics,
Radboud University Nijmegen Medical Centre, Nijmegen,
The Netherlands
* g.poelmans@psy.umcn.nl
Attention Deficit Hyperactivity Disorder (ADHD) is a
common neuropsychiatric disorder observed in children and
adults. The disorder is characterised by inappropriate levels of
hyperactive, impulsive and inattentive behaviours that lead to
significant clinical and psychosocial impairments. ADHD
belongs to the multifactorial disorders and is highly heritable.
Recently, the first genome-wide association studies (GWAS)
for ADHD have been published. Firstly, we compiled a list of
100 top single nucleotide polymorphisms (SNPs) in gene
regions from the three published GWAS for ADHD, taking
into account the reported SNPs with association at p <
5.00E-04. Secondly, we searched the literature for the
(proposed) function of these 100 candidate genes and tried to
functionally integrate them into one pathway. We found that
approximately 1 in 4 of the ADHD candidate genes emerging
from the GWAS for ADHD (i.e. 26 out of the 100 putative
ADHD candidate genes) fitted into a neurodevelopmental
pathway that links axonal guidance genes/proteins at the
synapse (such as the ROBO1, UNC5B, UNC5C, LPL,
CDH13, CTNNA2, NTRK3, ADCYAP1R1 and NUCB1
genes) with several downstream-acting adaptor and (neuronal)
cytoskeleton associated genes/proteins (such as the FHIT,
NEDD4L, SEC14L4, VWC2L, RAB1B, MBOAT1, EREG,
PPM1F, RBM35A, MAP1B, MOBP, DNM1, ITGA11,
MMP24 and SPOCK3 genes) and eventually results in
neuronal migration, i.e. directed neurite outgrowth.
In summary, we have identified a common eurodevelopmental
pathway that may provide an important contribution to the
understanding of ADHD etiology.

O4.3 RISK PATHWAYS OR PLEIOTROPIC EFFECTS?
AN INVESTIGATION INTO COGNITIVE
INTERMEDIATE PHENOTYPES CONTRIBUTING TO
THE ASSOCIATION BETWEEN COMT VAL158MET
GENOTYPE AND ANTISOCIAL BEHAVIOUR IN
CHILDREN WITH ADHD
K. Langley* (1), J. Heron (2), M. O'Donovan (1), M. Owen
(1), A. Thapar (1)
1. MRC Centre for Neuropsychiatric Genetics & Genomics,
Cardiff University 2. ALSPAC, Dept of Social Medicine,
University of Bristol
* langleyk@cardiff.ac.uk
As replicated genetic susceptibility loci for psychiatric
disorders are identified, it becomes necessary to investigate
the mechanisms through which such genotypes exert their
effect. One proposal is to identify intermediate phenotypes
lying on the risk pathway between genotype and outcome.
An association between the COMT Val158Met polymorphism
in the presence of ADHD and antisocial behaviour has been
independently replicated in three separate studies and pooled
analysis. We replicated this association in a further sample,
then investigated the role of two potential intermediate
phenotypes; executive functioning and “Social cognitive
dysfunction” (lack of empathy and awareness of others’
emotions). Utilising data from the prospective longitudinal
ALSPAC sample of children aged eight years old, (n=4365)
we replicated previous findings that Val/Val genotype in the
presence of ADHD is associated with increased antisocial
behaviour (beta=0.07, t=4.47, p=3x10-6). Measures of
executive function were associated with both the COMT
Val/Val genotype (p=0.02 to p

O5 GENETIC OVERLAP
O5.1 COPY NUMBER VARIATION AND GENE
DOSAGE CHANGES IN AUTISM: OVERLAP WITH
REGIONS INVOLVED IN SCHIZOPHRENIA AND
BIPOLAR DISEASE
M. Smith (1), P. Flodman (1), J. Gargus (1), M. Simon (1), J.
Heck (1), D. Wallace (1)
1. University of California, Irvine
We utilized AFFYMETRIX SNP 6.0 microarrays to search for
genome copy number variants (CNV) in autism. We
discovered rare large CNV and smaller structural variants.
Microarray studies revealed the presence of deletion of 4Mof
chromosome 12p and duplication of 4M of 2p in siblings with
autism. Follow-up FISH studies revealed an unbalanced
chromosome translocation between2p and 12p in each sib.
Adjacent genes hemizygously deleted in this sib pair include
the CACNA1C voltage gated ion channel gene, ion channel
CACNA2D andERC2 neurotransmitter release gene.
CACNA1C has been implicated in other cases of autism and
in association studies of bipolar disorder. In a subject with
autism and aggression we identified of a 2q37.3 chromosome
deletion and duplication on5q33-q34 that included 5 GABA
receptor loci, GABRA1, GABRG2, GABRA6, GABRB2,and
GABRP. This chromosome region has been implicated in the
etiology of schizophrenia in a number of different studies. In a
subject with autism and seizures we confirmed presence of a
deletion of 15q13.3 that leads to loss of a number of genes
including CHRNA7 neurotransmitter receptor gene. Deletions
in this region have been implicated in seizure disorder, mental
retardation and in schizophrenia. Smaller structural variants in
our autistic subjects occur predominantly in genes active at the
synapse, in signal transduction and mitochondrial function.
O5.2 ABCA13: A CANDIDATE GENE FOR
SCHIZOPHRENIA AND BIPOLAR DISORDER
D. Blackwood* (1), H. Knight (2), B. Pickard (3), A. Maclean
(2), M. Malloy (2), D. Soares (3), A. McRae (4), A. Condie
(5), A. White (5), W. Hawkin (5), K. McGhee (2), M. van
Beck (1), D. Macintyre (1), J. Starr (6), I. Deary (7), P.
Visscher (4), D. Porteous (3), R. Cannon (8), D. St. Clair (9),
W. Muir (2)
1. Division of Psychiatry, University of Edinburgh, Royal
Edinburgh Hospital, Edinburgh, EH10 5HF, UK
2. Division of Psychiatry, University of Edinburgh, Royal
Edinburgh Hospital, Edinburgh, EH10 5HF, UK; Medical
Genetics, Institute of Genetics and Molecular Medicine,
University of Edinburgh, Molecular Medicine Centre, Western
General Hospital, Crewe Road 3. Medical Genetics, Institute
of Genetics and Molecular Medicine, University of Edinburgh,
Molecular Medicine Centre, Western General Hospital, Crewe
Road, Edinburgh, EH4 2XU, UK 4. Queensland Institute of
Medical Research, 300 Herston Road, Herston 4006, QLD,
Australia 5. Wellcome Trust Clinical Research Facility,
Western General Hospital, Crewe Road, Edinburgh,
EH4 2XU, UK 6. Centre for Cognitive Ageing and Cognitive
Epidemiology, Geriatric Medicine unit, University of
Edinburgh, Royal Victoria Hospital, Craigleith Road,
Edinburgh, EH4 2DN, UK 7. Centre for Cognitive Ageing and
Cognitive Epidemiology, Department of Psychology,
University of Edinburgh, 7 George Square, Edinburgh, EH8
9JZ, UK 8. Cancer Biology Group, National Center for
Toxicogenomics, NIEHS, Research Triangle Park,
North Carolina 27709, USA 9. Institute of Medical Sciences,
University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD,
UK
* d.blackwood@ed.ac.uk
We investigated the brain expressed lipid transporter gene
ABCA13 for a role in mental illness after showing it was
directly disrupted by a breakpoint in a complex chromosome
abnormality involving chromosomes 7 and 8 in a person with
chronic schizophrenia. Sequencing ABCA13 exons in 100
cases with schizophrenia and 100 controls revealed rare
coding variants including one nonsense and nine missense
mutations specific to or more common in schizophrenia. These
10 variants were assayed in additional cohorts of patients with
schizophrenia (~1000) bipolar disorder (~600) and controls
(~2000) and their frequency was greater than controls in
schizophrenia (OR=1.93, p=0.0057) and bipolar disorder
(OR=2.71, p=0.00007). In the next stage we examined for the
presence of each of the 10 variants in the families of carriers.
106 members of 21 families took part and family size ranged
from 3 to 16. Non-parametric single point linkage analysis
using MERLIN to estimate identity by descent (IBD)
between all pairs of affected relatives showed significant
linkage of ABCA13 mutations to a phenotype including
schizophrenia, bipolar disorder and major depression
(LOD=4.38; p=3.5 x 10-6). These findings establish a role for
ABCA13 and lipid biology in schizophrenia and bipolar
disorder and also demonstrate that different rare penetrant
variants in one gene may cause either schizophrenia, bipolar
disorder or major depression in different families.

O5.3 RARE COPY NUMBER VARIANTS: A POINT OF
RARITY IN GENETIC RISK FOR BIPOLAR
DISORDER AND SCHIZOPHRENIA?
D. Grozeva* (1), G. Kirov (1), D. Ivanov (2), I. Jones (1), L.
Jones (3), E. Green (1), D. StClair (4), A. Young (5), N.
Ferrier (5), A. Farmer (6), P. McGuffin (6), W. Wellcome
Trust Case Control Consortium (7), P. Holmans (2), M. Owen
(1), M. O'Donovan (1), N. Craddock (1)
1. MRC Centre for Neuropsychiatric Genetics and Genomics,
Department of Psychological Medicine, School of Medicine,
Cardiff University, Heath Park, Cardiff, CF14 4XN, United
Kingdom 2. MRC Centre for Neuropsychiatric Genetics and
Genomics, Biostatistics and Bioinformatics Unit, Department
of Psychological Medicine, School of Medicine, Cardiff
University, Heath Park, Cardiff, CF14 4XN, United Kingdom
3. Department of Psychiatry, University of Birmingham,
National Centre for Mental Health, 25 Vincent Drive,
Birmingham, B15 2FG, United Kingdom 4. University of
Aberdeen, Institute of Medical Sciences, Foresterhill,
Aberdeen AB25 2ZD, United Kingdom 5. School of
Neurology, Neurobiology and Psychiatry, Royal Victoria
Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1
4LP, United Kingdom 6. SGDP, The Institute of Psychiatry,
King's College London, De Crespigny Park, Denmark Hill,
London SE5 8AF, United Kingdom 7. Wellcome Trust Case
Control Consortium
* GrozevaDV@cf.ac.uk
Recent studies suggest that copy number variation in the
human genome is extensive and may play an important role in
susceptibility to disease, including neuropsychiatric disorders
such as schizophrenia and autism. The possible involvement
of copy number variants (CNVs) in Bipolar disorder (BD) has
received little attention to date. We sought to determine
whether large (>100kb) and rare (found in > 1% of the
population) CNVs are associated with susceptibility to BD and
to make comparisons with findings in schizophrenia.
We performed a genome-wide survey for CNVs in 1697 BD
patients and 2806 healthy controls from the Wellcome Trust
Case Control Consortium, using the Affymetrix 500K array.
The burden of large CNVs (≥1Mb) in BD was not increased
compared with controls, and was significantly less than in
schizophrenia cases. CNVs previously implicated in the
aetiology of schizophrenia were not more common in cases.
Schizophrenia and bipolar disorder differ with respect to CNV
burden in general, and association with specific CNVs in
particular. Our data are consistent with the possibility that
possession of large rare deletions may modify the phenotype
in those at risk of psychosis: those possessing such events are
more likely to be diagnosed with schizophrenia; those without
such events are more likely to be diagnosed with bipolar
disorder.
O5.4 BETA-CATENIN PROMOTER CHIP-CHIP
REVEALS POTENTIAL SCHIZOPHRENIA AND
BIPOLAR DISORDER GENE NETWORK
E. Pedrosa (1), A. Shah (1), C. Villa (1), C. Tenore (2), M.
Capogna (3), H. Lachman* (1)
1. AECOM 2. SUNY, Binghamton 3. Boston College
*lachman@aecom.yu.edu
Therapeutic concentrations of lithium salts inhibit GSK3β and
phosphoinositide (PI) signaling suggesting that abnormal
activation of these pathways could be a factor in bipolar
disorder (BD) pathogenesis. Involvement of these pathways is
also supported by recent genome wide association (GWA)
studies. One way investigators have tried to understand the
molecular basis of BD and the therapeutic action of lithium is
by microarray expression studies, since the signal transduction
pathways affected by the drug are coupled to transcriptional
activation and inhibition. However, expression profiling has
some limitations and investigators cannot use the approach to
carry out analyses on fetal brain tissue, arguably the most
relevant biological structure related to BD pathogenesis. In
addition, the relative contribution of PI and GSK3β signaling
in mediating the effects of lithium on gene expression cannot
be assessed by simply analyzing lithium-treated cells. To
address these shortcomings, we have taken a novel approach
to help understand lithium’s effect on gene expression using
chromatin immunoprecipiation-enriched material annealed to
microarrays (ChIP-chip) targeting genes in fetal brain tissue
bound by β-catenin, a transcription factor that is directly
regulated by GSK3β. The promoters for several hundred genes
were found to bind β-catenin, many of which are
schizophrenia (SZ) and BD candidate genes, including four
(PLXNA2, CACNA1B, NRNG and NOTCH4 CACNA1B)
that were identified as candidates in recently published GWA
studies. The findings suggest that seemingly disparate
candidate genes for SZ and BD can be incorporated into a
common molecular network revolving around SK3β/β-catenin
signaling. In addition, the finding that a subgroup of SZ
candidate genes may be influenced by a lithium-responsive
pathway could have therapeutic implications.

O5.5 WHOLE-GENOME ANALYSIS REVEALS AN
OVERLAPPING GENETIC BASISFOR BIPOLAR
DISORDER, MAJOR DEPRESSION, AND
SCHIZOPHRENIA
T. Schulze* (1), N. Akula (1), R. Breuer (2), M. Nalls (3), M.
Nöthen (4), S. Cichon (4), A. Singleton (3), M. Rietschel (2),
Bipolar Genome Study (BiGS) Consortium (1), F. McMahon
(1)
1. NIMH 2. CIMH (Mannheim, Germany) 3. NIA 4. Life &
Brain, University of Bonn (Germany)
* schulzet@mail.nih.gov
Family, linkage, and association studies have long suggested
some shared genetic basis for major psychiatric disorders. We
used genome-wide association study (GWAS) data from the
Genetic Association Information Network (GAIN) bipolar
disorder study (n=2064), the Wellcome Trust Case
Control Consortium (WTCCC) bipolar disorder sample
(n=4840), a German bipolar GWAS data set (n=2066), the
GAIN major depression study (n=3573), and the GAIN
schizophrenia data set (n=2729) in order to test for genetic
relationships among these disorders. A Parkinson Disease
GWAS (n=537) dataset was included as a negative control.
We weighted each SNP by the association results in a
specified discovery sample and then assigned a score to each
individual on the basis of the weighted burden of risk alleles
(WBRA) across all SNPs in a specified test sample. Using the
WBRA derived from the GAIN bipolar sample, we could
discriminate cases from controls in the WTCCC sample (p =
2.5 x 10-10) with a predictive accuracy (as expressed by the
area under the curve; AUC) of 0.55. The same WBRA
discriminated cases from controls in the German bipolar
(p=4.6 x 10-8; AUC=0.57) and the GAIN major depression
sample (p=7.32 x 10-7; AUC=0.57). Conversely, the WBRA
derived from the WTCCC bipolar sample predicted
schizophrenia affection status with a similar accuracy (p=2.9 x
10-9; AUC=0.56). In contrast, the WBRA derived from the
GAIN bipolar sample, had no predictive value in the
Parkinson Disease dataset (AUC= 0.50, p=ns). These results
confirm formal genetic evidence that major psychiatric
disorders share largely overlapping sets of risk alleles, which
are distinct from those that predispose to a neurological
disorder such as Parkinson Disease.
O6 SCHIZOPHRENIA 1
O6.1 DUPLICATION AND DELETION AT 15Q11.2 ARE
ASSOCIATED WITH SCHIZOPHRENIA
Q. Zhao (1), G. Feng (2), K. Huang (1), Z. Zhang (1), X. Zhao
(3), T. Li (1), G. He (1), T. Wang (1), Z. Zeng (1), D. St Clair
(4), L. He (1), Y. Shi (1)
1. Bio-X Center and Bio-X Center Affiliated Changning
Mental Health Center, Shanghai Jiao Tong
University, Shanghai, PR China; 2. Shanghai Institute of
Mental Health, Shanghai, PR China; 3. Institutes of
Biomedical Sciences, Fudan University Shanghai, PR China;
4. Department of Mental Health, University of Aberdeen;
Schizophrenia is a severe mental disorder marked by
hallucinations, delusions, cognitive deficits and apathy, with a
heritability estimated at 73–90%. However genetic variants
involved are proved difficult to understand. In recent years,
SNP chips led to the quick identification of copy number
variatons (CNVs). As a result, rare copy number variations
have been found to be important risk factors of schizophrenia.
One of the those promissing loci is the CNV at 15q11.2,
including four genes, TUBGCP5, CYFIP1, NIPA2 and
NIPA1. TUBGCP5 is specific expressed in the subthalamic
nuclei while the latter three are widely expressed in the central
nervous system. Deletion of the four genes was implicated in
delayed motor and speech development, behavioural problems
and lower intellectual ability in PWS/AS patients. A recent
study showed that microdeletion at this loci was significant
associated with schizophrenia. In the present work, we
screened this CNV in 1568 unrelated paranoid schizophrenia
patients and 1728 randomly-chosen normal controls in total
by affymetrix 500K/6.0 SNP arrays or RT-PCR then validated
by MLPA and Taqman assays in the Chinese Han population.
We detected 8 deletions in cases and 1 in controls in total
(OR=8.95, p=0.012). We found that the CNV at 15q11.2 were
significantly associated with schizophrenia (p=8.51×10-5).
Our data provided further evidence that deletion at 15q11.2 is
a risk factor and suggested that duplication at this loci was
also implicated in the pathogenesis of schizophrenia in
Chinese Han population. Our findings also supported the
incomplete penetrance of duplication and deletion at this loci.

O6.2 STRUCTURAL IMAGING REVEALS NOVEL
GENETIC INFLUENCES IN SCHIZOPHRENIA
J. Turner* (1), J. Segall (2), G. Guffanti (1), V. Calhoun (2),
H. Bockholt (2), S. Potkin (1), F. Macciardi (1), F. BIRN (1)
1. University of California, Irvine 2. MIND Research Network
* turnerj@uci.edu
Purpose. We combined grey matter volumetric measures with
GWS data to identify genetic influences on grey matter loss
which are different in schizophrenia than in age- and
gender-matched healthy subjects. Methods. One hundred
fifty-four subjects either with schizophrenia (SZ) or healthy
volunteers (HV) were part of a larger study for the Functional
Imaging Biomedical Informatics Research. They were scanned
with an MP-RAGE or equivalent protocol, using a mixture of
1.5T and 3T scanners. Mean grey matter density measures
over standard anatomical regions which were significantly
different between groups were combined into a set of 14
quantitative traits (QT). Blood samples were genotyped using
the Illumina HumanHap300 BeadArray. Each QT and single
nucleotide polymorphism was analyzed in a general linear
model to identify significant interactions (p < 10-6) between
genotype and diagnosis on the phenotype. Results. The
anterior cingulate and frontal medial areas both identified
interactions with ADAMTS18 (16q23.1); frontal medial areas
also showed a significant interaction with the MPRIP gene
(17p11.2). The frontal inferior and middle regions identified
areas in strong linkage disequilibrium with PRKCB1 and
CHP2 (16p12.1). The superior temporal gyrus identified the
CDKAL1 gene (6p22.3). Conclusions. Imaging genetics
analyses in schizophrenia have identified neurodevelopmental
and stress-related genetic effects on a functional phenotype;
using structural phenotypes identifies genes known to be
involved in inflammatory disorders (ADAMTS18, CDKAL1),
metabolic disorder (PRKCB1, CHP2), regulation of synaptic
transmission (PRKCB1), and stress actin fibers (MPRIP).
These provide a picture of multiple interacting genetic
influences on regional grey matter loss found in the disorder.
O6.3 CLINICAL AND COGNITIVE ASSOCIATIONS
AND DATA MINING EVIDENCE OF EPISTASIS IN
THE NIMH/GCAP SCHIZOPHRENIA GWA STUDY
R. Straub* (1), Y. Iizuka (1), N. Feng (1), C. Li (1), B.
Kolachana (1), K. Vakkalanka (1), M. Egan (2), D. Dickinson
(1), D. Weinberger (1)
1. GCAP, NIMH, NIH 2. Merck Pharmaceuticals
* straubr@intra.nimh.nih.gov
We genotyped part of our GCAP sample - 270 controls, 197
schizophrenia trios (115 with an unaffected sibling), and 55
additional schizophrenics - with ILLUMINA 550k/610k chips,
and downloaded 3 Illumina iControl genotype datasets and
GAIN Schizophrenia genotypes from dbGAP. We ran TDT
and case-control tests of association to the clinical phenotype
and QTDT and regression analyses of a range of quantitative
phenotypes in patients and controls, including cognition, EEG,
fMRI, and TPQ. Genome wide analyses of the effects of risk
associated SNPs on expression and expression correlation
patterns were performed using our own expression database
and publicly available databases, and potential biochemical
interactions between genes investigated by pathway analysis.
Two statistical approaches were used to examine genetic
interactions. First we ran genome wide SNP-SNP case-control
epistasis analysis. The most significant GCAP result (PLINK
Epistasis p=4.53e-10) was between NOS1 and LRP2, each of
which physically bind to the known susceptibility gene
NOS1AP (CAPON). Numerous other interactions involving
known susceptibility genes were also observed. Second, we
used the data mining programs RANDOM FOREST and
TREENET from Salford Systems (San Diego, CA) to identify
SNPs potentially involved in higher order interactions
influencing clinical risk. After imputation of a random subset
(522 schiz., 600 controls) of the GAIN (“GRU” of the
MGS-EA) sample, we mined 332,236 SNPs in parallel in the
GCAP (252 schiz, 270 controls) and GAIN samples. In
GCAP, a set of 4430 SNPs (median PLINK Genotypic
case-control p=0.1028) within or closest to 2868 genes were
strongly predictive of group (TREENET 10-fold cross
validation test ROC 0.987, schiz. prediction error 0.06, control
prediction error 0.07). In GAIN, a set of 4371 SNPs SNPs
within or closest to 2865 genes were strongly predictive of
GAIN group (TREENET test ROC 0.956, schiz prediction
error 0.11, control prediction error 0.12). By chance,
prediction error and prediction success are each 0.50, and only
a fraction of these SNPs are likely to be tagging schizophrenia
susceptibility genes. Nevertheless, we found that at both the
SNP and gene level there was overlap between the two
independent samples: 60 SNPs were in common, 182 genes
had multiple SNPs from both samples closest to them, and 139
of these had SNPs within them, and within 100kb in both
studies. The initial pathway analysis (INGENUITY
SYSTEMS, Redwood CA) of 131 of these showed 22
potentially involved in protein-protein (PP) interactions, in 7
groups: [CACNA1D, RYR2, HOMER, PARK2, PACRG,
GRIA1], [ATXN1, A2BP1, FAT4, EIF4ENIF1], [PDZD2,

CTNND2, MAGI2], [ERC2, PCLO], [MAGI1, RPS6KA2],
[PLXNA2, SEMA3A], and [GABRG3, GABRG2, GABRB3].
Addition of just 4 PP “bridges” (CACNA1C, GRID2, DLG4,
and NOVA1) connect the first 4 groups, which then include
additional genes (eg. CDH13, ODZ2, NRG3, DPP6, KCNH4)
from the 131, totalling 26. In contrast, genes from the top 131
genome wide TDT SNPs, and the top and bottom 131 case
control SNPs contained only 5, 4 and 6 PP interactors
respectively, and these were not merged by adding single
bridges. Our integrated database of clinical, cognitive, and
data mining results also contains genes from the literature,
tracking about 400 specific genes/regions. We have confirmed
many prior gene findings, and some of the more interesting
functional pathways we are filling out are indicated by the
following selections, many of which are novel with regard to
SNP association to schizophrenia : ASTN2, AUTS2,
CAMTA1, CDH8, CMYA5, CNTN4, CNTNAP2, CSMD1,
CSMD3, CSNK1A1L, CTNNA2, CTNNA3, DMD, DOCK2,
ESRRG, FHIT, FSHR, GUCY1A2, GUCY1A3,
HLA-DRB1/DRB5, HS3ST1, HS3ST3A1, MAD1L1, NBAS,
ODZ4, OFCC1, OSBPL3, PINK1, PKHD1, PSMD13,
PTPRD, PTPRG, RTP4, S100A7/S100A6, SGCZ,
SLC10A2, SLC24A3, SLIT3, ST8SIA3, TLE3, UNC5C.
Ongoing work includes typing the remainder of our sample
(503 schiz total, 600 controls) with the ILLUMINA 660W
chip, epistasis analysis and data mining of additional
independent samples, and detection of CNVs with the
AGILENT 1x1M chip. A multilevel, integrative approach
fundamentally acknowledging the genotypic and phenotypic
heterogeneity and epistasis inherent in the condition, and
building on prior findings is essential to properly evaluate and
utilize GWA results, and we think that this has produced many
new candidates, each supported by multiple pieces of
evidence.
O6.4 ASSOCIATION OF THE DISOCIDIN DOMIAN
RECEPTOR 1 WITH POSITIVE YMPTOMATOLOGY
IN SCHIZOPHRENIC PATIENTS
S. de la Portilla (1), J. Valero (1), M. Cortes (1), B. Roig (1),
E. Vilella* (1)
1. HPUIPM, IISPV, URV
* elisabet.vilella@urv.cat
We recently published a genetic association between the
discoidin domain receptor 1 (DDR1) gene and schizophrenia
(Roig et al. 2007). DDR1 is a tyrosine kinase receptor present
in the myelin sheath of CNS axons (Franco-Pons et al, 2006).
Moreover, we showed that the rs1049623 expression in
lymphocytes is genotype dependent (Roig et al. 2007). In the
present work we explore possible influence of SNP
rs1049623 on clinical variables. A total of 125 patients with a
DSMIV schizophrenia diagnosis were evaluated with the
positive and negative syndrome scale (PANSS). Patients with
DDR1 SNP rs1049623 GG genotype have higher scores in
delusions (P=0.004), excitement (P=0.03), grandiosity
(P=0.001) and positive subscale (P=0.041) and lower scores in
emotional and social withdrawal (P=0.26 and 0.01
respectively) and total negative subscale (P=0.044). In the
psychopathological subscale GG genotype was also associated
with lower scores in disorientation (P=0.002), and disturbance
of volition (P=0.03) and higher scores in lack of judgment and
insight (P=0.03). No statistical differences were obtained for
the total items of the PANSS. These data demonstrates that
patients with the GG genotype punctuated differently in the
PANSS scale and therefore a possible causal relationship
between DDR1 and schizophrenia may exist.

O6.5 ASSOCIATION OF 5HT2C RECEPTOR
POLYMORPHISMS WITHPSYCHOPATHOLOGY
AND TREATMENT RESPONSE IN SCHIZOPHRENIA
H. Meltzer* (1), K. Jayathilake (1), H. Hashimoto (2)
1. Vanderbilt University School of Medicine 2. Graduate
School of Pharmaceutical Sciences, Osaka University
* herbert.meltzer@vanderbilt.edu
The serotonin (5-HT) 2C receptor has important tonic
inhibitory effects on dopamine release in brain areas critical
to schizophrenia, including the frontal cortex, nucleus
accumbens and ventral tegmentum. We will report an
association between the 5-HT2C receptor polymorphisms
rs3813929 (-759C/T), rs518147 (-697G/C), both of which are
promoter polymorphisms, and rs6318 (Cys23Ser), a disputed
functional SNP, and baseline psychopathology and response to
treatment in Caucasian and Afro-American patients with
schizophrenia (or schizoaffective disorder). The Ser23 allele
carriage was strongly associated with higher baseline scores of
the BPRS psychosis subscale (p = 0.007) and total (p
= 0.01) scores. The SNP -759C/T was also significantly
associated with the psychosis subscale (p = 0.04). The
haplotype (-759C)–(-697C)–(23Ser) (p = 0.00091) and
(-759C)–(23Ser) (P = 0.00055) were strongly associated with
BPRS psychosis subscale. In addition, the Ser23 allele
carriage was significantly associated with improvement in
negative symptoms following 6 weeks and 6 month APD
treatment. The relationship of these SNPs to cognitive
dysfunction and its amelioration will also be reported.
O6.6 COPY NUMBER VARIATIONS OF
SCHIZOPHRENIA SUSCEPTIBILITY LOCI
ARE ASSOCIATED WITH A SPECTRUM OF SPEECH
AND DEVELOPMENTAL DELAYS AND BEHAVIOR
PROBLEMS
T. Sahoo* (1), J. Rosenfeld (1), L. Shaffer (1)
1. Signature Genomic Laboratories
* sahoo@signaturegenomics.com
Although the etiology of schizophrenia is not well understood,
a genetic predisposition is presumed to be a determinant of
susceptibility to the disease. Recently, microarray-based
comparative genomic hybridization (aCGH) and other
molecular techniques have identified novel copy number
variants (CNVs) in individuals with schizophrenia. We
undertook a “genotype-first” analysis of individuals with
microdeletions and microduplications overlapping ~30
putative schizophrenia susceptibility loci among individuals
referred to our laboratory with developmental or growth delay,
birth defects, and/or behavior problems. After excluding
individuals with CNVs commonly associated with
schizophrenia (e.g., microdeletion of 22q11.21) and those with
CNVs encompassing but substantially larger than those
reported in the literature, we identified CNVs involving 10
susceptibility loci among 52 individuals. In 18 individuals the
CNVs encompassed or disrupted developmental pathway
genes. None of the individuals had schizophrenia as an
indication for study. The phenotypes included developmental
and speech delay and behavioral problems, including
obsessive behavior in a few. Of the 21 cases where parental
studies were possible, the CNV was inherited in 14 and de
novo in 7. Additionally, a search for significant aCGH
findings in individuals referred for testing for schizophrenia
identified six with CNVs, including one with a
microduplication of the 22q11.21 DiGeorge syndrome region
and one with a microdeletion at 16p12.2, which has been
identified in individuals referred for autistic features. Our
results suggest CNVs across schizophrenia susceptibility loci
are often associated with phenotypes that minimally overlap
with schizophrenia, and additional factors are likely required
to lead to the development of schizophrenia.

O7 MOOD DISORDERS 2
O7.1 COPY NUMBER VARIATION AT 15Q11.2 ARE
ASSOCIATED WITH BIPOLAR DISORDER AND
MAJOR DEPRESSION IN CHINESE HAN
POPULATION
Y. Shi* (1), Q. Zhao (1), L. He (1)
1. Bio-X Center, Shanghai Jiao Tong University
* shiyongyong@gmail.com
Bipolar disorder and major depressive disorder are related to a
distinct change of mood. Bipolar disorder is a relatively
common psychiatric disease which is characterized by mood
symptoms of mania and depression with a heritability
estimated at 62~80%. Major depressive disorder is
characterized by sadness or irritability and accompanied by at
least several psychophysiological changes. Early-onset,
severe and recurrent depression may have a higher heritability
than other forms of depression. Up till now, Rrare copy
number variations emerged as important risk factors of several
major psychiatric disorders, and some of them could be risk
factors for different diseases. One of the most promissing loci
is the CNV at 15q11.2. 15q11.2 spans, including four genes,
namely TUBGCP5, CYFIP1, NIPA2 and NIPA1. Deletions in
this loci locus was commonly found in Prader-Willi
Syndrome/Agenleman Syndrome patients. And, Aa recent
study showed that schizophrenia was associated with
microdeletion at this loci. was significant associated with
schizophrenia. In the present work, we screened this CNV in
1448 unrelated bipolar disorder patients, 1317 unrelated major
depressive disorder patients (no sign of bipolar disorder
symptoms during two-year track after onset) and 1728 normal
controls in total by affymetrix 500K/6.0 SNP arrays or
RT-PCR then validated by MLPA or Taqman assays. We
found that the CNV at 15q11.2 were significantly associated
with bipolar disorder ( p=7.4×10-5 ) and major depressive
disorder ( p=1.95×10-4 ). Our data suggested that this CNV,
including both microdeletions and duplications at this locus, is
awere shared risk factor of bipolar disorder and major
depressive disorder in Chinese Han population. Our findings
also supported the incomplete penetrance and phenotypic
diversity of duplication and deletioncopy number variations at
this locilocus.
O7.2 GENETICS OF DIURNAL CORTISOL
SECRETION: A GENOME WIDE ASSOCIATION
STUDY.
F. Velders* (1), M. Kumari (2), C. Kirschbaum (3), A.
Hofman (4), F. Verhulst (1), C. van Duijn (4), H. Tiemeier (1)
1. Department of Child and Adolescent Psychiatry, Erasmus
MC – Sophia Children’s Hospital, Rotterdam, The
Netherlands 2. Department of Epidemiology and Public
Health, London, United Kingdom 3. Department of
Psychology, Technical University of Dresden, Dresden,
Germany 4. Department of Epidemiology, Erasmus MC
University Medical Center, Rotterdam, The Netherlands
* f.velders@erasmusmc.nl
Introduction: Genes involved in the Hypothalamic Pituitary
Adrenal (HPA) axis regulation are potential candidate genes
for psychiatric disorders. Although several genes are known to
be involved in the regulation of the HPA axis, the relationship
of variations in these genes with diurnal cortisol secretion is
not very robust. In search of new candidate genes for
psychiatric disorders, we performed a Genome Wide
Association Study (GWAS) of diurnal cortisol secretion.
Methods: The GWAS study was performed in an ongoing
population-based cohort of 1711 elderly persons, using the
Illumina Platform 550k v.3.0. Cortisol secretion was measured
in 4 saliva samples obtained on one day and was expressed as
the area under the curve. To replicate our results, we repeated
analyses of top hits in 3000 participants of the Whitehall II
Study. Findings: Top hits were found on chromosome 15
(rs8026512, beta -0.57, p-value 6*10e-06), chromosome 3
(rs2252459, beta 0.53, p-value 8.8*10e-06) and in the FKBP5
gene region on chromosome 6 (rs9470080, beta -0.55, p-value
1*10e-05), a known candidate gene for depression. FKBP5
SNPs were associated with anxiety in participants of the
Rotterdam Study. We did not replicate any cortisol top hits in
the Whitehall II Study. Interpretation: The present
population-based study shows that the glucocorticoid receptor
co-chaperone FKBP5 is related to diurnal cortisol secretion
and anxiety in the elderly. This extends previous FKBP5
studies on treatment response in depressed patients. However,
our approach to utilize cortisol data to identify new candidate
genes for psychiatric disorders was less successful.

O7.3 CRY2 IS A KEY TO DEPRESSION
C. Lavebratt (1), L. Sjöholm* (1), P. Soronen (2), T. Paunio
(2), M. Vawter (3), W. Bunney (4), R. Adolfsson (5), . Forsell
(6), J. Wu (4), J. Kelsoe (7), T. Partonen (8), M. Schalling (1)
1. Karolinska Institutet at Karolinska University Hospital
Solna, Department of Molecular Medicine and Surgery,
Stockholm, Sweden 2. National Institute for Health and
Welfare; Department of Chronic Disease Prevention; Public
Health Genomics Unit, Helsinki, Finland 3. University of
California Irvine School of Medicine, Functional Genomics
Laboratory, Irvine, California, USA 4. University of
California Irvine School of Medicine Department of
Psychiatry & Human Behavior, Irvine, California, USA
5. Division of Psychiatry, Department of Clinical Sciences,
University of Umeå, Umeå, Sweden 6. Department of Public
Health Science, Karolinska Institutet at Karolinska University
Hospital Solna, Stockholm, Sweden 7. University of
California San Diego School of Medicine, Department of
Psychiatry, La Jolla, California, USA 8. National Institute for
Health and Welfare; Department of Mental Health and
Substance Abuse Services; Mood, Depression and Suicidal
Behaviour Unit, Helsinki, Finland
* louise.sjoholm@ki.se
Abnormalities in the circadian clockwork characterize major
depressive and bipolar disorders. Circadian clock genes are
targets of interest in these patients. CRY2 is a circadian gene
that participates in regulation of the evening oscillator. This is
of interest in depressive disorders where a lack of switch from
evening to morning oscillators has been postulated. We
observed a marked diurnal variation in human CRY2 mRNA
levels from peripheral blood mononuclear cells and a
significant upregulation following one-night total sleep
deprivation. In depressed bipolar patients, levels of CRY2
mRNA were decreased and a complete lack of increase was
observed following sleep deprivation, a known antidepressant.
To investigate a possible genetic contribution we undertook
SNP genotyping of the CRY2 gene in two independent
population-based samples from Sweden and Finland. The
CRY2 gene was significantly associated with winter
depression in both samples. A difference in risk haplotype
identity between the two samples narrowed the suggestive
region of the vulnerability locus. Taken together we propose
that CRY2 harbors a vulnerability locus for depression, and
that mechanisms of action involve dysregulation of CRY2
expression.
O7.4 GENOME-WIDE ASSOCIATION STUDY OF
UNIPOLAR DEPRESSION IN THE UK POPULATION
C. Lewis* (1), M. Ng (1), A. Butler (1), S. Cohen-Woods (1),
K. Pirlo (1), R. Uher (1), K. Aitchison (1), S. Heath (2), M.
Lathrop (2), N. Craddock (3), M. Owen (3), A. Korszun (4), L.
Jones (5), I. Jones (3), M. Barnes (6), P. Muglia (6), G. Breen
(1), I. Craig (1), A. Farmer (1), P. McGuffin (1)
1. MRC SGDP Centre, Institute of Psychiatry, King’s College
London, De Crespigny Park, London, SE5 8AF, U.K.
2. Centre National de Génotypage, 91057 Evry, France
3. Department of Psychological Medicine, Cardiff University,
School of Medicine, Heath Park, Cardiff, CF14 4XN, U.K.
4. Centre for Psychiatry, Wolfson Institute of Preventive
Medicine, Barts and The London, Charterhouse Square,
London, EC1M 6BQ, U.K. 5. Division of Neuroscience,
Department of Psychiatry, University of Birmingham, The
Barberry, 25 Vincent Drive, Edgbaston, Birmingham, B15
2FG, U.K. 6. GlaxoSmithKline, R&D
* cathryn.lewis@kcl.ac.uk
Unipolar depression has substantial heritability with a
postulated genetic contribution, but genome-wide association
studies (GWAS) and candidate gene studies published to date
have failed to convincingly identify susceptibility genes. We
performed a GWAS using 1636 cases of depression
ascertained in the UK, and 1594 controls, screened negative
for psychiatric disorders. Cases were collected as part of an
affected sibling pair linkage study for recurrent depression
(DeNt; N=332), a case-control study for recurrent depression
(DeCC; N= 1346) and a pharmacogenetic study (GENDEP;
N=88). Cases and controls were genotyped on the
Illumina Human610-Quad BeadChip. After applying stringent
QC criteria for missing genotypes, departure from
Hardy-Weinberg equilibrium, and low minor allele frequency,
we tested for association to depression using logistic
regression, correcting for population ancestry. Two SNPs
(separated by 7 kb) attained p-values of < 5 x 10^-7, and two
further SNPs (in different regions) had p-values of < 5 x
10^-6. In the region with the most strongly associated SNPs,
evidence of association strengthened to genome-wide
significance when genotypes at HapMap markers were
imputed using MACH (p = 6x10^-9, taking into account
imputation uncertainty). At the most significant genotyped
SNP, the minor allele conferred a protective effect (OR 0.72;
case frequency 0.185, control frequency 0.235). This GWAS
of recurrent depression cases and screened controls has
identified strong evidence for a previously unknown gene and
several suggestive associations for further exploration in other
samples.

O7.5 GWAS ASSOCIATION STUDY OF CIRCADIAN
GENES SUPPORTS ARNTL AS A
MORNINGNESS-EVENINGNESS LOCUS
C. Nievergelt (1), R. McKinney (1), J. Kelsoe (1), D. Kripke
(1), Bipolar Genome Study (BiGS)
1. Department of Psychiatyr, University of California, San
Diego
Objective: Prior studies have reported associations of various
circadian clock genes with psychiatric and sleep disorder
phenotypes. We conducted a comprehensive search of
genomic loci influencing circadian morningness-eveningness
preference, using a large European American GWAS sample
of bipolar disorder cases assembled by the Bipolar Disorder
Genetics (BiGs) Consortium. Methods: Circadian
morningness-eveningness preference as determined by the
13-item Basic Language Morningness scale (BALM) were
available for a subset of 948 participants previously genotyped
on the Affymetrix 6.0 SNP array. Primary analysis focused on
333 SNPs in 32 candidate circadian-rhythm-related genes.
Results: A significant association was found between the
BALM and rs1026070 at 11p15 in ARNTL (p < 0.016,
Bonferroni corrected for 333 comparisons), which was
supported by two other SNPs in this gene being nominally
associated with this trait. Subjects homozygous for the rare
CC genotype had a mean (±SD) morningness score of 28
(11.31) compared to 29.79 (9.72) for CG and 33.11 (9.33) for
the GG genotypes. A genome-wide analysis including over
700K SNPs found the strongest statistical evidence for BALM
association with rs1000078 in CDH13 (p = 7.09 x 10-6) at
16q23 and rs8089008 in an intergenic region at 18q22 (p =
1.34 x 10-5). The best circadian marker, rs1026070 in
ARNTL, ranked 21st among the 700K SNP markers, though
none were significant at the genome-wide level. Discussion:
Several lines of evidence have repeatedly associated ARNTL
with psychiatric and sleep disorder phenotypes and suggest
that ARNTL polymorphisms influence behavioral circadian
preference.
O7.6 GENOME-WIDE ASSOCIATION STUDY OF
TEMPERAMENT AS AN INTERMEDIATE
PHENOTYPE FOR BIPOLAR DISORDER
T. Greenwood* (1), H. Akiskal (1), Bipolar Genome Study
(BiGS), J. Kelsoe (1)
1. Department of Psychiatry, University of San Diego and the
San Diego VA Healthcare System, San Diego, CA
* tgreenwood@ucsd.edu
Despite the many attempts that have been made to identify
genes for bipolar disorder (BD) there has been limited success,
which has generally been attributed to genetic heterogeneity
And small gene effects. However, it is also possible that the
categorical phenotypes currently used in genetic studies of BD
are not the most informative, efficient, or biologically
relevant. Although quantitative phenotypes provide an
alternative to categorical phenotypes based on DSM diagnosis,
they have not been fully exploited in BD genetics, largely due
to a lack of easily accessible biological measures. As a
quantitative phenotype for BD we have explored the use of
temperament, a heritable personality factor that establishes a
person’s baseline level of reactivity, mood, and energy. We
hypothesize that the fundamental trait that is inherited is not
BD but rather variations in temperament with more extreme
temperamental variation conferring greater susceptibility to
developing BD. To investigate this theory, we have performed
a genome-wide association study using genotype data from the
NIMH Bipolar Genome Study (BiGS) and 1191 bipolar
subjects that completed the Akiskal Temperment Scale
(TEMPS-A), which is designed to access lifelong, milder
aspects of bipolar symptomatology. Five temperaments are
defined by this scale: hyperthymic, dysthymic, cyclothymic,
irritable, and anxious. Of these, the hyperthymic and
dysthymic temperaments produced the most interesting
genome-wide results with peak pvalues of 6.2X10-8 on
chromosome 12 and 2.4X10-7 on chromosome 4,
respectively. These results suggest that aspects of
temperament may have utility as intermediate phenotypes for
BD.

O8 SCHIZOPHRENIA 2
O8.1 MATERNAL HSV2 INFECTION INTERACTS
WITH NMDA GENE POLYMORPHISMS IN THE
OFFSPRING INFLUENCING THE RISK OF
SCHIZOPHRENIA
D. Demontis* (1), H. Buttenschön (2), M. Nyegaard (1), A.
Hedemand (1), C. Pedersen (3), T. Flint (2), K. Sørensen (4),
M. Nordentoft (5), B. Nørgaard-Pedersen (4), T. Werge (6), P.
Andersen (4), D. Hougaard (4), P. Mortensen (3), O. Mors (2),
A. Børglum (1)
1. Institute of Human Genetics, Aarhus University, Aarhus,
Denmark 2. Centre for Psychiatric Research, Aarhus
University Hospital, Risskov, Aarhus, Denmark 3. National
Centre for Register-based Research, University of Aarhus,
Aarhus, Denmark 4. Department of Clinical Biochemistry,
State Serum Institute, Copenhagen, Denmark 5. Psychiatric
Centre Bispebjerg, Copenhagen NV, Denmark 6. Research
Institute of Biological Psychiatry, Sct. Hans Hospital,
Roskilde, Denmark
* ditte@humgen.au.dk
Schizophrenia (SZ) is a complex disorder, caused by genetic
and environmental factors. The genes (GRIN1, GRIN2A,
GRIN2B, GRIN2C and GRIN2D) encoding the
N-methyl-D-aspartate receptor (NMDAR) have been found to
associate with SZ in some studies. Glutamate receptors are
expressed early in human brain development, and
environmental factors such as maternal infection could impact
on NMDA function in the fetus. We used 85 tag-SNPs in the
five genes to test for association with SZ, in three Danish
samples in total consisting of 986 individuals with SZ and
1501 control persons. We investigated if maternal herpes
simplex type 2 (HSV2) infection increases offspring risk of SZ
later in life depending on GRIN-gene variation, by testing for
tag-SNPs interaction in the offspring with maternal HSV2
antibody level during pregnancy.
Significant allelic association with SZ was found for 11 SNPs
out of 32 SNPs in GRIN2B. One SNP remained significant
after Bonferroni correction (rs1806194, p=0.00094). When
testing for interaction between genetic variation and maternal
HSV2 infection eight GRIN2B and two GRIN2A SNPs
showed significant interaction. Three SNPs in GRIN2B
remained significant after Bonferroni correction
(rs1805539, rs1806201, rs1806205, p=0.00142-0.00024).
Our results suggest that GRIN2B may be a risk gene for SZ
and that maternal HSV2 infection interacts with GRIN2B in
the offspring, affecting the risk of SZ. The NR2B subunit,
encoded by the GRIN2B gene is mainly present in immature
neurons in the early postnatal brain. It is possible that early
life distortion of NMDAR function caused by dysregulation of
GRIN2B due to maternal HSV2 infection could be important
for the preposition to SZ.
O8.2 EXON-BASED RE-SEQUENCING ANALYSIS OF
THE SCHIZOPHRENIA SUSCEPTIBILITY GENE
NRXN1
T. Mühleisen* (1), A. Forstner (1), F. Basmanav (1), V.
Nieratschker (2), R. Breuer (2), S. Moebus (3), M. Rietschel
(2), M. Nöthen (1), S. Cichon (1)
1. Institute of Human Genetics, Department of Genomics, Life
& Brain Center, University of Bonn, Bonn, Germany
2. Department of Genetic Epidemiology, Central Institute of
Mental Health, Mannheim, Germany 3. Institute for Medical
Informatics, Biometry and Epidemiology, University Hospital
of Essen, University Duisburg-Essen, Essen, Germany
* thomas.muehleisen@uni-bonn.de
Exon-disrupting copy number variants (CNVs) in the neurexin
1(NRXN1; 2p16.3) gene were recently found to be
significantly over-represented in schizophrenia patients
(Rujescu, Ingason et al. 2009), supporting previous findings of
two microdeletions in schizophrenia patients involving this
gene (Kirov et al. 2008; Walsh et al. 2008). Deletions and
duplications of variable sizes accumulated in the promoter
region and the first exons. The gene product NRXN1 is a
presynaptic scaffolding molecule which plays an important
role in neurotransmission by interacting with neurexophilins
and neuroligins. In the present study, we performed
re-sequencing at the NRXN1locus to identify rare genetic
variations - single base exchanges (SBEs) or small
deletions/duplications - which might confer susceptibility to
schizophrenia and are likely to be missed using common
single nucleotide polymorphisms in genome-wide association
studies. We investigated 96 patients (51% males, parents
available) with a DSM-IV diagnosis of schizophrenia and 96
sex-matched controls, all of German descent. Using the
Sanger method, we re-sequenced all coding sequences and
splice sites of the NRXN1isoforms alpha1, alpha2 and beta,
totaling ~10kb per individual. We have finished re-sequencing
in ~50% of the sample and observe an over-representation of
rare SBEs in patients (n=4) versus controls (n=1). We are
currently analyzing the second half of the sample. All
identified rare variants are being investigated by
bioinformatical tools and databases. They will be tested for
inheritance from their parents, too, and followed-up in
extended samples of schizophrenia patients and controls.

O8.3 GENOME-WIDE ASSOCIATION STUDY OF
REGIONAL BRAIN VOLUME IN 600 INDIVIDUALS
SUGGESTS INVOLVEMENT OF KNOWN
PSYCHIATRY CANDIDATE GENES, IDENTIFIES
NEW CANDIDATES FOR PSYCHIATRIC DISORDERS
AND POINTS TO POTENTIAL MODES OF THEIR
ACTION
B. Franke* (1), M. Rijpkema (2), A. Arias Vasquez (1), J.
Veltman (3), H. Brunner (3), P. Hagoort (4), G. Fernandez (4)
1. Department of Human Genetics and Department of
Psychiatry, Donders Institute for Brain, Cognition and
Behavior, Radboud University Nijmegen Medical Centre,
Nijmegen, The Netherlands 2. Donders Centre for Cognitive
Neuroimaging, Donders Institute for Brain, Cognition and
Behavior, Radboud University Nijmegen, Nijmegen, The
Netherlands 3. Department of Human Genetics, Radboud
University Nijmegen Medical Centre, Nijmegen, The
Netherlands 4. Donders Centre for Cognitive Neuroimaging,
Donders Institute for Brain, Cognition and Behavior, Radboud
University Nijmegen, Nijmegen, The Netherlands
*b.franke@antrg.umcn.nl
Though most psychiatric disorders are highly heritable, it has
been hard to identify genetic risk factors involved, which are
most likely of small individual effect size. A possible way to
aid identification of risk genes is the use of intermediate
phenotypes. These are supposed to be closer to the biological
substrate(s) of the disorder than psychiatric diagnoses, and
therefore less genetically complex. Intermediate phenotypes
can be defined e.g. at the level of brain function and of
regional brain structure. Both are highly heritable, and
regional brain structure is linked to brain function. Within the
Brain Imaging Genetics (BIG) study at the Radboud
University Nijmegen (Medical Centre) we performed a
genome-wide association study (GWAS) in 600 of the
currently 1100 healthy study participants. For all BIG
participants, structural MRI brain images were available. Gray
and white matter volumes were determined by brain
segmentation using SPM software. FSL-FIRST was used to
assess volumes of specific brain structures. Genotyping was
performed on Affymetrix 6.0 arrays. Results implicate known
candidates from earlier GWAS and candidate gene studies in
mental disorders in the regulation of regional brain structure.
E.g. polymorphisms in CDH13, featuring among the
top-findings of GWAS in disorders including ADHD,
addiction and schizophrenia, were found associated with
amygdala volume. The ADHD candidate gene SNAP25 was
found associated with caudate nucleus volume.
In conclusion, the use of intermediate phenotypes based on
(subcortical) brain volumes may shed more light on pathways
from gene to disease, but can also be expected to facilitate
gene identification in psychiatric disorders.
O8.4 ASSOCIATION OF A FUNCTIONAL
HAPLOTYPE OF THE POST-SYNAPTIC DENSITY 95
(PSD-95) GENE WITH SCHIZOPHRENIA
M. Cheng (1), D. Liao (2), J. Chen (3), Y. Wang (3), I. Lai (3),
Y. Liou (3), C. Chen (2)
1. Institute of Medical Sciences, Tzu-Chi University, Hualien,
Taiwan 2. Division of Mental Health and Addiction
Medicine, Institute of Population Health Sciences,
National Health Research Institutes, Zhunan, Taiwan
3. Department of Psychiatry, Yuli Veterans Hospital, Hualien,
Taiwan
There is compelling evidence supporting the association of
hypofunction of the N-methyl-D-aspartate (NMDA)
receptor with the pathophysiology of schizophrenia.
Post-synaptic density protein 95 (PSD-95) binds to NMDA
receptors and plays an essential role in regulating the activity
of the NMDA receptor. Altered expression of PSD-95 in
various brain regions in patients with schizophrenia has been
reported in several postmortem studies. This study aimed to
investigate whether there are variants of the PSD-95 gene that
may confer an increased risk of schizophrenia. We
re-sequenced the promoter region, all the exons (including 5’
and 3’ UTR) and their flanking intronic sequences of the
PSD-95 gene in a sample of Han Taiwanese schizophrenic
patients (n=434) and control subjects (n=438), and conducted
an association study. We also characterized the function of
several genetic polymorphisms of PSD-95 using a reporter
gene assay. We did not detect any mutations at the
protein-coding regions associated with schizophrenia of the
PSD-95 gene in this sample. Nevertheless, we identified a
specific haplotype at the promoter region of the PSD-95 gene
that was nominally associated with schizophrenia
(odd ratio: 1.24, 95% confidence interval: 1.01-1.52). The
reporter gene assay showed that this haplotype had
significantly greater activity than the other haplotypes. Our
study provides genetic evidence to indicate that the PSD-95
gene is associated with schizophrenia, and the increased gene
expression of PSD-95 may be involved in the pathophysiology
of schizophrenia.

O8.5 GENOME-WIDE ASSOCIATION STUDY (GWAS)
OF SCHIZOPHRENIA IN A LARGE GENETICALLY
HOMOGENEOUS IRISH POPULATION
The Schizophrenia Genomics Ireland Consortium*, The
Wellcome Trust Case Control Consortium
* acorvin@tcd.ie
Schizophrenia (SZ; OMIM 181500) is a complex genetic
disorder of substantial heritability. Three recent genome-wide
association studies (GWAS) provide support for several
common susceptibility loci, including the HLA-region (The
International Schizophrenia Consortium (ISC), 2009; Shi et
al, 2009; Stefansson et al, 2009). Additionally, the ISC study
reported evidence that ~30% of susceptibility can be explained
by common risk variants, many of which are likely to be of
small effect. Combining datasets may increase power to
discover small effects, but may be compromised by individual
differences in study design, ascertainment, phenotyping,
population stratification or genotyping platforms.
We report a large SZ GWAS performed as part of WTCCC2
of 2,357 cases and 2,000 controls from the ethnically
homogeneous Irish population. The study also accesses 6,000
additional controls from the UK. All cases were collected
using similar study design and ascertainment procedures
including a structured clinical interview (SCID) and consensus
diagnosis procedure. This dataset has ≥80% power to detect
allelic odds ratios (ORs) 1.2-1.3 with minor allele frequency
(MAF) 0.2-0.3. Combining data with existing GWAS studies
may also allow sequential discovery of additional risk
variants. GWAS data was analysed using the Affymetrix 6.0
array. For all samples passing Affymetrix’s laboratory QC,
raw intensities (from the .CEL files) were renormalized within
collections using CelQuantileNorm (see
http://outmodedbonsai.sourceforge.net/). These normalized
intensities were used to call genotypes with an updated version
of the Chiamo software (see
www.stats.ox.ac.uk/~marchini/software/gwas/chiamo.html),
adapted for Affymetrix 6.0 SNP data. Primary analysis of the
GWAS data will be presented with p-values from 1-df
Cochran-Armitage tests for trend. REFERENCES 1. The
International Schizophrenia Consortium. Common polygenic
variation contributes to risk of schizophrenia and bipolar
disorder. Nature. 2009 Jul 1. PMID: 19571811. 2: Shi J, et al.
Common variants on chromosome 6p22.1 are associated with
schizophrenia. Nature. 2009 Jul 1. PMID: 19571809. 3.
Stefansson H, et al. Common variants conferring risk of
schizophrenia. Nature. 2009 Jul 1. PMID:19571808.
O8.6 ZNF804A: SCHIZOPHRENIA RISK ALLELE
ASSOCIATED WITH NEUROANATOMIC,
COGNITIVE, AND CLINICAL PHENOTYPES
T. Lencz* (1), P. Szeszko (1), P. DeRosse (1), K. Burdick (1),
A. Malhotra (1)
1. The Zucker Hillside Hospital
* lencz@lij.edu
A recent genomewide association study identified a novel
SNP in ZNF804A (rs1344706) as a risk factor for
schizophrenia (O’Donovan et al. 2008; Nat Gen, 40:1053-5).
In a functional MRI study, this SNP was associated with
abnormal patterns of neural connectivity (Esslinger et al.
2009; Science, 324:605). To further functionally characterize
this SNP, we tested rs1344706 for association with phenotypes
that include brain structure, neurocognitive performance, and
clinical symptomatology. We first assessed the relationship of
rs1344706 to risk for illness in our sample of Caucasian
patients with schizophrenia/schizoaffective disorder (n=277)
and Caucasian controls (n=247). Allele frequencies matched
those in the original sample of O’Donovan et al. (2008) and
confirmed an association with illness; T allele frequency was
66% in cases vs 59% in controls (?2=4.3, p

O9 EARLY CAREER INVESTIGATOR
TRACK: CANDIDATE GENES,
EPIGENETICS, AND PHENOMICS
O9.1 THE VAL 158 MET POLYMORPHISM IN THE
COMT GENE IS ASSOCIATED WITH DEPRESSION
AND MOTIVATION
E. Åberg* (1), L. Sjöholm (1), Y. Forsell (2), C. Lavebratt (1)
1. Department of Molecular Medicine and Surgery, CMM,
Karolinska Institutet at Karolinska University Hospital Solna,
Stockholm, Sweden 2. Department of Public Health Science,
Karolinska Institutet at Karolinska University Hospital
Solna, Stockholm, Sweden
* elin.aberg@ki.se
Environmental risk factors together with genetic vulnerability
create a complex background to develop depression. In this
study we investigate the association between the Val158Met
polymorphism in the COMT gene and depression by using a
Swedish population-based longitudinal study (PART). We
also investigate if the polymorphism could be involved in the
low motivational level found in depressed individuals. The
PART study includes data from childhood to adulthood and
contains scales on psychological well being. We found that
depressed people displayed a lower frequency of the val/val
genotype than controls (OR=1.50, 95% CI=1.11-2.02,
P=0.0096). In analysis of men and women separately, the
association was found among men only (OR=2.26, 95% CI=
1.26-4.05, p=0.0086). Regression analysis including potential
risk factors for depression further indicated that the genotypes
met/met or met/val was associated with depression (P=0.01).
Since COMT is involved in dopamine metabolism and is
expressed in brain areas important for the brain reward
system, we thought that variations in this gene could be
involved in motivational disturbances. Individuals with the
met/met or met/val genotype had more negative motivation
symptoms (MDI scale) than individuals homozygous for the
val-allel (P=0.01). Further, regression analyses including risk
factors for depression showed that individuals with the
genotype met/met or met/val had more negative motivation
symptoms than individuals with the val/val combination
(P=0.007). In conclusion, the COMT-polymorphism
Val158Met has so far primarily been associated with
schizophrenia, working memory and anxiety related
behaviour. We can in this study present that variations in the
COMT-gene is associated with depression and motivation.
O9.2 RE-SEQUENCING ANALYSIS OF THE
SCHIZOPHRENIA-ASSOCIATED MICRODELETION
REGION ON 1Q21.1
F. Basmanav* (1), A. Forstner (1), J. Freudenberg (2), L.
Priebe (1), M. Alexander (1), V. Nieratschker (3), R. Breuer
(3), S. Moebus (4), M. Rietschel (3), M. Nöthen (1), T.
Mühleisen (1), S. Cichon (1)
1. Institute of Human Genetics, Department of Genomics, Life
& Brain Center, University of Bonn, Bonn, Germany 2. Center
of Genomics and Human Genetics, Feinstein Research
Institute, New York, USA 3. Department of Genetic
Epidemiology, Central Institute of Mental Health, Mannheim,
Germany 4. Institute for Medical Informatics, Biometry and
Epidemiology, University Hospital of Essen, University
Duisburg-Essen, Essen, Germany
* basmanav@uni-bonn.de
We and others have recently identified rare microdeletions on
chromosome 1q21.1 as the strongest genetic risk factor for
schizophrenia known to date (odds ratio ~15). In the present
study, we aimed to explore to what extent common and rare
susceptibility variants in the region spanned by the
microdeletion might contribute to the disease allele spectrum.
Analysis of common SNPs was done using Illumina HH550
data and did not provide evidence for association with
schizophrenia. To identify potential rare coding variants, we
applied an exon-based re-sequencing approach covering seven
RefSeq genes and three predicted genes. Approximately 25 kb
of sequence information per individual were generated from
96 DSMIV-diagnosed schizophrenia patients (derived from
parent-offspring trios) and 96 sex-matched controls.
Re-sequencing has been completed for 50% of the sample and
provides some evidence for an over-representation of
previously unknown exonic single base exchanges in patients
(n=5 in 48 patients and n=1 in 48 controls). Two of the rare
variants detected in patients represent non-synonymous amino
acid changes with a predicted effect on protein structure, one
is a stop mutation. We hypothesize that such rare exonic single
base changes may contribute to the schizophrenia disease
allele spectrum at this particular locus. We are currently
analysing the second half of the sample. All rare variants
identified in the patients will be tested for parental inheritance
and will be followed-up in large, independent samples of
schizophrenia patients and controls. F.B.Basmanav and
A.J.Forstner contributed equally to this work.

O9.3 FAMILIAL FORMS OF PSYCHIATRIC
DISORDERS IN A LARGE, NATIONALLY
REPRESENTATIVE SAMPLE
N. Low* (1)
1. McGill University
* nancy.low@mcgill.ca
Introduction: Evidence from clinical populations of mood and
anxiety disorders has demonstrated familial aggregation.
Clinical characteristics of the familial forms of disorders have
also been described (egs, earlier age of onset, worse
impairment, treatment refractoriness). These findings require
confirmation in population-based samples where the majority
of the burden of illness rests. Examination of the specificity of
the familial clinical characteristics across the disorders is also
understudied. Sample: The Canadian Community Health
Survey was cross-sectional survey of 36,984 subjects
randomly selected from the population of household residents.
The response proportion nationally was 77%. Subjects were
interviewed in-person using Composite International
Diagnostic Interview which included family history. Statistical
Analyses: Multivariable logistic regression models were
constructed to identify clinical characteristic variables
associated with a family history of depression, mania, panic
and social phobia. Results: Earlier age of onset and age of 1st
consultation were common to all the familial forms. Earlier
age of 1st treatment was associated with all familial forms
except social phobia. Comorbid disorders: social phobia and
panic were associated with mood disorders; PTSD was
associated with the anxiety disorders, but not mood disorders;
psychosis was associated with depression only. Current
medication use: anxiolytics and antidepressants was associated
with all forms except mania; antipsychotics were associated
the mood disorders; mood stabilizers were associated with
depression, but not mania. Additionally, familial depression
was associated with stressful precipitants, suicide attempts,
impairment, and number of consultants seen. Conclusion: The
familial forms of depression, mania, panic and social phobia
have common and unique clinical characteristics.
O9.4 RESPONSE TO LITHIUM IN BIPOLAR
DISORDER: INTER-RATER RELIABILITY AND
DISTRIBUTIONAL PROPERTIES
M. Manchia* (1), C. Consortium on Lithium Genetics (2), I.
International Group for The Study of Lithium Treated Patients
(3), M. Alda (1)
1. Department of Psychiatry, Dalhousie University, Halifax,
Nova Scotia, Canada 2. www.ConLiGen.org 3.
http://www.igsli.org
* mirko.manchia@cdha.nshealth.ca
The Consortium on Lithium Genetics (ConLiGen) has been
created with the aim to investigate the genetic basis of
response to lithium prophylaxis in more than 1,200 bipolar
patients followed in research centers across the world. In this
context, it is important to assess the key phenotypic measures
and the response to long-term lithium treatment reliability
across the participating centres. To this end, we measured the
inter-rater reliability of the response definition based on a 0-10
scale published and validated previously (Grof et al. 2002,
Garnham et al. 2007). 23 investigators from 8 participating
sites rated 12 standardized case vignettes. We analyzed the
concordance of ratings by means of Kappa (?) and intra-class
correlation coefficient (ICC). In addition, we performed
mixture analysis of the empirical distribution of the total scale
score from a sample of 623 patients studied previously.
Kappa scores and ICC showed a good level of agreement
across sites (?=0.67, z=36.87; ICC=0.73). Leaving out the
clear cut non-responders (score=0), modelling of score
distribution suggested the presence of a best fitting model of
two normal curves (1 component: ?2= 32.1, p0.05) with the following parameters:
partial responders (mean=3.1, SD=1.5, proportion=0.36) and
full responders (mean=7.7, SD=1.6, proportion=0.64) and
suggested cut-off for full response ≥6. These findings indicate
a good inter-rater reliability of assessments of the response to
lithium and provide analytical support for the definition of the
full response phenotype. These results will be used in a
subsequent genome wide association study of the ConLiGen
samples.

O9.5 PROFILING EPIGENETIC CHANGES IN THE
BRAIN ASSOCIATED WITH SCHIZOPHRENIA,
BIPOLAR DISORDER, AND MAJOR DEPRESSIVE
DISORDER
E. Dempster (1), J. Mill (1), C. Wong (1), S. Docherty (1), R.
Pidsley* (1)
1. MRC Social, Genetic and Developmental Psychiatry
Centre, Institute of Psychiatry, King’s College, London, UK
* ruth.pidsley@kcl.ac.uk
Traditional aetiological studies of psychiatric conditions have
focused primarily on the interplay between genetic and
environmental risk factors. However, a growing body of
evidence suggests that epigenetic factors also play an
important role in mediating susceptibility to psychiatric
conditions. Epigenetics refers to heritable changes in genomic
function, which are not caused by changes in the nucleotide
sequence of the DNA. DNA methylation is one of the most
stable and well-characterised forms of epigenetic control.
Whilst studies of epigenetic dysfunction in neuropsychiatric
conditions are in their infancy, research to date indicates that
there may be widespread DNA-methylation changes in the
brains of affected patients. In this study we used a unique
collection of post-mortem brain samples to identify
DNA-methylation changes associated with schizophrenia,
bipolar disorder and major depressive disorder. We used a
candidate gene-approach to focus specifically on the
DNA-methylation status across a set of genes that have been
previously implicated in psychiatric conditions via
transcriptomic and gene association studies. We used a
highly-sensitive DNA methylation profiling strategy to assess
epigenetic variation across the known promoter regulatory
regions of these genes to detect epigenetic changes associated
with disease. Our studies uncovered evidence of DNA
methylation changes in several genes, either globally or at
specific CpG sites, with a number of psychiatric patients being
clear epigenetic outliers.
O9.6 DIRAS2 IS ASSOCIATED WITH ADULT ADHD
AND RELATED PERSONALITY TRAITS
A. Reif* (1), L. Weissflog (1), T. Nguyen (2), C. Jacob (1), M.
Romanos (1), S. Liedel (1), H. Schäfer (2), A. Warnke (1), B.
Cormand (3), J. Haavik (4), B. Franke (5), K. Lesch (1)
1. University of Würzburg 2. University of Marburg 3.
University of Barcelona 4. University of Bergen 5. University
of Nijmegen
* Reif_A@klinik.uni-wuerzburg.de
Attention-deficit/hyperactivity disorder (ADHD) is a clinically
heterogeneous childhood behavioral neurodevelopmental
disorder which is highly persistent into adulthood and often
goes along with substantial comorbidity. Although it is
assumed that adult ADHD (aADHD) has an even higher
genetic background than childhood ADHD, studies on the
genetics of aADHD are scarce. Linkage analyses and
genome-wide association studies (GWAS) identified several
susceptibility loci for this genetically complex disorder. The
9q22 region has been detected by both linkage and GWAS as
a candidate locus for ADHD (Lesch et al., 2008; Zhou et al.,
2008). This region contains the GTP-binding RAS-like 2 gene
(DIRAS2; MIM: 607863) which is expressed in the basal
ganglia and the cerebellum. The function of the gene product
is still unknown but might include the regulation of cell
morphogenesis. As DIRAS2 thus can be considered a
positional as well as functional candidate gene for ADHD, we
conducted a case-control association study in 624 patients
suffering from adult ADHD diagnosed according to
DSM-IV criteria and 424 controls recruited in the Lower
Franconia area in Germany, all of Caucasian origin. Six out of
the 14 tested SNPs covering all haplotype blocks of DIRAS2
were associated with ADHD, with nominal p-values ranging
from p= 0.009 to p= 0.01. Two of these SNPs were also
associated with NEO Extraversion and TPQ Harm Avoidance
in affected subjects. Within each of two haploblocks, there
was one associated haplotype. A replication attempt is
currently made in the IMpACT sample, consisting of an
additional 1,000 patients from The Netherlands, Norway and
Spain. Our findings in adult ADHD are confirmed by a
family-based study on childhood ADHD (166 families, 576
children), where SNPs in the gene were also associated with
disease. These findings indicate consistently that DIRAS2
may play a role in the pathomechanisms of ADHD.
Re-sequencing of the gene as well as functional studies will be
required to further explore the role of DIRAS2 in ADHD.

O9.7 A LONGITUDINAL STUDY OF EPIGENETIC
VARIATION IN TWINS
C. Wong* (1), A. Caspi (2), B. Williams (2), A. Ambler (1),
T. Moffitt (2), J. Mill (1)
1. 1-MRC Social, Genetic and Developmental Psychiatry
Centre, Institute of Psychiatry, King’s College, London, UK
2. 1-MRC Social, Genetic and Developmental Psychiatry
Centre, Institute of Psychiatry, King’s College, London, UK;
2- Departments of Psychology and Neuroscience, Psychiatry
and Behavioral Sciences, and Institute for Genome Sciences
and Policy Duke University
* chloe.wong@kcl.ac.uk
Twin studies have been widely used to provide an estimate of
the relative contribution of genetic and environmental factors
to phenotypic traits. In many psychiatric conditions, it is
commonly observed that monozygotic (MZ) twins are more
concordant than dizygotic (DZ) twins, strongly implicating
inherited genetic factors in pathogenesis. Given that MZ twins
are assumed to be genetically identical, any discordance
between the twins is attributed to ‘non-shared’ environmental
factors in the classical twin-study approach. Emerging
evidence suggests that epigenetic factors, such as DNA
methylation, may also contribute to phenotypic
discordance between genetically identical individuals.
Few studies have investigated the extent of epigenetic
variation between genetically-identical individuals, and no
study has yet investigated longitudinal changes in DNA
methylation of MZ and DZ twins. In this study we assessed
the level of within-pair epigenetic discordance in a sample of
MZ and DZ twins pairs (MZ=46; DZ=45) obtained from the
Environmental-Risk Study, in which samples from the same
individuals were collected at two different time-points (age 5
and 10). The levels of DNA methylation across seven
candidate genes related to psychiatric disorders were
quantified using high-resolution bisulfite-based mapping.
Significant gene-specific DNA methylation differences were
observed within both MZ and DZ twin-pairs at both age 5 and
10. Moreover DNA methylation was shown to change
dynamically over-time. Findings from this study will allow us
to elucidate the contribution of genetic and environmental
factors to longitudinal changes in DNA methylation and will
have implications for understanding the causes of phenotypic
lability.
O9.8 INTERACTION BETWEEN CRHR1 GENE AND
CHILDHOOD TRAUMA PREDICTS ADOLESCENT
DEPRESSIVE AND ANXIETY SYMPTOMS
K. Thode* (1), R. Olvera (1), C. Walss-Bass (1), D.
Williamson (1)
1. UTHSCSA
* thode@uthscsa.edu
The role of the hypothalamic-pituitary-adrenal (HPA) axis in
stress-related psychiatric disorders has been well-established.
Recent research identified an interaction between a SNP
(rs1876831) in the CRH receptor 1 (CRHR1) gene and
stressful life events for heavy alcohol use in adolescents. We
identified a CRHR1 promoter SNP (rs12938031) that
predicted increased HPA axis response to CRH stimulation.
The aims of our current study were to examine rs12938031's
relationship to rs1876831 as well as whether they moderate
the effects of exposure to stress for symptoms of depression
and anxiety in adolescents. Data were available from the Teen
Alcohol Outcomes Study (TAOS), an ongoing cohort study
examining alcohol use in adolescents. A total of 340
adolescents aged 12-15 years (184 males, 156 females), were
genotyped, and a subset of 321 completed the Childhood
Trauma Questionnaire (CTQ) assessing lifetime stressful
events and self-report questionnaires measuring depressive
and anxiety symptoms. rs12938031 and rs1876831 were
found to be in high linkage disequilibrium (D’0.951, LOD
35.6, r2 0.388). Adolescents carrying the major A allele of
rs12938031 reported greater depressive symptoms in relation
to higher CTQ scores than adolescents homozygous for the
minor G allele (p=0.002). Females with high CTQ scores
reported more depressive symptoms compared to males
regardless of genotype (p=0.012). Adolescents carrying the
minor T allele of rs1876831 reported greater anxiety
symptoms in relation to higher CTQ scores than adolescents
homozygous for the major C allele (p=0.015). These results
provide further evidence for genetic moderation of the stress
response directly involving SNPs in the CRHR1 gene.

O10 MOOD DISORDERS 3
O10.1 ASSOCIATION BETWEEN DISTRACTIBILITY
AND P2RX7 IN SWEDISH BIPOLAR DISORDER
PATIENTS
L. Backlund (1), P. Nikamo (2), L. Frisén (3), I. Römer Ek
(1), L. Träskman-Bendz (4), H. Ågren (5), G. Edman (6), M.
Landén (1), M. Schalling (2), U. Ösby (1)
1. Dpt Clin Neurosc, Karolinska Institutet, Stockholm,
Sweden 2. Div Neurosc, Dpt Mol Med and Surg, Karolinska
Institutet, Stockholm, Sweden 3. Div of Psych, Dpt Clin Sc,
Karolinska Institutet, Danderyd Univ Hosp, Stockholm,
Sweden 4. Div Psych, Dpt Clin Sc, Univ Hosp, Lund, Sweden
5. Sahlgrenska Ac,Univ Gothenburg, Inst Neurosc and
Physiol, Sweden 6. Dpt Psych, R&D Sect, Danderyd Univ
Hosp, Sweden
Introduction: Bipolar disorder is a severe psychiatric disorder
(heritability around 80%). At least a dozen genes have been
shown to be involved in the etiology, although replication has
been difficult. We investigated 36 SNPs and their association
with different symptoms in bipolar disorder. Methods: A
Swedish sample of 646 patients with bipolar disorder (BP1:
79%, BP2: 21%), was phenotyped with lifetime assessment of
specific symptoms of mania and depression and analyzed with
36 SNPs in the genes S100A10, BDNF, P2RX7, CANKK2,
DAOA, SLC6A4, ADRBK2 and COMT. At first, 171 patients
were analyzed. A second set of 475 patients was used for
replication. Genotyping was carried out with Applied
Biosystems TaqMan using ABI PRISM 7900HT Sequence
Detecting System. Statistical analysis (Chi-square tests) was
performed with the Unphased program 3.0.10. Results: The
manic symptom distractibility (set 1: 44%, set 2: 59%, total:
52 %) was significantly associated with two SNPs in the
P2RX7 gene coding for a purinergic ATP-binding channel
implicated in calcium-signaling and neurotransmitter release,
rs1718119 (set 1: p=0.016, set 2: p=0.006, total p=0.0001,
OR=1.7) and rs1621388 (set 1: p=0.038, set 2: =0.054, total:
p=0.001, OR=1.4). No other consistent associations with
distractibility were found. Conclusions: Genetic associations
were identified between distractibility and two SNPs in the
P2RX7 gene in Swedish bipolar patients. These two SNPs are
7 kb and 0.4 kb away from the rs2230912, previously
associated with bipolar disorder. These SNPs might be
associated to dysfunctional P2RX7 receptors and therefore
impairment of neurotransmitter systems implicated in bipolar
disorder.
O10.2 THE INTERACTION BETWEEN SEROTONIN
TRANSPORTER GENE (SLC6A4) SINGLE
NUCLEOTIDE POLYMORPHISMS (SNPS) AND
DEPRESSION RISK FACTORS
Z. Samaan* (1), C. Xie (1), M. Zhang (1), B. Keavney (2), J.
Engert (3), G. Pare (1), S. Rangarajan (1), A. Rosengren (4),
K. Sliwa (5), M. Zubaid (6), S. Yusuf (1), S. Anand (1),
Interheart Investigators
1. McMaster University 2. Newcastle University 3. McGill
University 4. Sahlgrenska University 5. Chris Hani
Baragwanath Hospital 6. Kuwait University
* samaanz@mcmaster.ca
Hypothesis: The relationship between genetic variants and
depression is mediated by depression risk factors (DRF).
Background: Genetic studies of depression have lacked
consistency at least partly due to the heterogeneous nature of
depression. We investigated the association between SLC6A4
variants and DRF. Methods: The INTERHEART study was
conducted in 52 countries and identified myocardial infarction
(MI) risk factors. A sub-sample (n = 8717, 80% male) from 5
ethnic groups (South Asian, European, Arab, Iranian and
Nepalese) was studied for depression (based on DSM IV
criteria). Ten SNPs from SLC6A4 were genotyped and tested
for association with depression, DRF, and MI using a
dominant model adjusted for ethnicity, age and sex. Results:
Depression occurred in 1002 (12%) individuals. DRF
included: smoking, stressful life events, chronic disease (i.e.
prior stroke, diabetes), unemployment, sleep, locus of control
and BMI. Five SNPs were associated with sleep (rs1042173,
rs4583306, rs7224199, rs3794808 and rs140701, p-values
range from 0.008-0.02) and history of stroke (p-values range
from 0.001-0.006). Two additional SNPs were associated
with BMI (rs16965628 p = 0.0007, rs2020933 p = 0.003).
rs2020942 was associated with MI (p = 0.0037) and showed a
trend with depression (p = 0.09). Analysis of SNP*DRF on
depression showed a significant interaction between
rs2020942 and sleep (p = 0.003, β -0.14) and rs140700 and
BMI (p = 0.0015, β 0.06). Conclusions: The association
between SLC6A4 variants and depression may be mediated in
part by its association with depression-related risk factors.

O10.3 GABAA RECEPTOR GENE VARIATION AND
SCHIZOAFFECTIVE DISORDER, BIPOLAR TYPE:
EVIDENCE IMPLICATING GABRR1
E. Green (1), D. Grozeva (1), V. Moskvina (1), M. Hamshere
(1), I. Jones (1), L. Jones (2), G. Kirov (1), I. Nikolov (1), D.
Vukcevic (3), S. Caesar (2), K. Gordon-Smith (2), C. Fraser
(1), E. Russell (1), D. St Clair (4), A. Young (5), N. Ferrier
(5), A. Farmer (6), P. McGuffin (6), Wellcome Trust Case
Consortium , P. Holmans (1), M. Owen (1), M. O'Donovan
(1), N. Craddock (1)
1. Cardiff University 2. University of Birmingham 3.
University of Oxford 4. University of Aberdeen
5. Newcastle University 6. Institute of Psychiatry
Previously, we have shown that variation in the GABAA
receptor genes, GABRB1, GABRA4, GABRB3, GABRA5
and GABRR3, influence risk for research diagnostic
Schizoaffective disorder, bipolar type (RDC SABP) in our
Wellcome Trust Case Consortium (WTCCC) bipolar disorder
genome-wide association study (GWAS) (279 RDC SABP
cases and 2938 controls). To ascertain if within our data any
additional GABAA receptor gene family members were
potentially associated with susceptibility to risk for RDC
SABP, we went on to examine the imputed GWAS data
(frequentist additive model). Ten genes were studied; omitting
the 5 previously identified associated genes, the 3 X
chromosome genes and GABRD on chromosome 1 for which
no SNPs were genotyped in our dataset. SNPs were selected
with a minor allele frequency > 1% and that were located
within the reference sequence or that lay within 20kb,
upstream and downstream, of the genes. Imputation provided
superior additional evidence for association with SNP
rs9451173 (frequentist additive p value = 1.5x10-4), an
intronic SNP within GABAA rho 1 gene (GABRR1). We
genotyped the rs9451173 polymorphism in a subset of our
WTCCC and new samples, 298 RDC SABP cases (279
WTCCC & 19 new) and 2270 controls (1442 WTCCC & 828
new). We observed a significant association for rs9451173, C
allele: cases, 7.1%; controls: 3.8%; Allelic p value = 4x10-4;
odds ratio OR, [95% CI] = 051, [0.36-0.74] Our findings
suggest that variation in GABRR1 gene potentially influences
risk for the RDC SABP phenotype.
O10.4 IDENTIFYING PANELS OF GENES FOR
GENETIC RISK PREDICTION IN BIPOLAR
DISORDER USING CONVERGENT FUNCTIONAL
GENOMICS
H. Le-Niculescu (1), S. Patel (1), D. Koller (1), J. Nurnberger
(1), N. Schork (2), A. Niculescu (3)
1. Indiana University 2. Scripps Research Institute 3. Indiana
University/ Indianapolis VA Medical Center
Mounting convergent evidence implicates many more genes in
complex disorders such as bipolar disorder than the small
number identified unambiguously by Genome-Wide
Association studies (GWAS) to date. We previously proposed
and provided proof of principle for the use of a
complementary approach, Convergent Functional Genomics
(CFG), as a way of mining the existing GWAS datasets for
signals that are there already, but did not reach significance
using a genetics-only approach. We have now extended our
previous work to include more datasets of GWAS, and more
recent evidence from other lines of work. In essence our
analysis is the most comprehensive integration of genetics and
functional genomics to date in the field of bipolar disorder,
identifying aseries of best candidate genes for bipolar disorder.
Moreover, we have put together, based on these top genes, a
comprehensive list of the best Single Nucleotide
Polymorphisms (SNPs). Panels of such SNPs can be used for
genetic testing for bipolar disorder before the illness manifests
itself. We have developed a Genetic Risk Prediction Score
(GRPS) based on such panels, and demonstrate how in an
independent test cohort for which we had both genotypic and
clinical information, the GRPS differentiates between patients
with bipolar disorder and normal controls. Such testing could
be used for diagnostics and personalized medicine approaches,
as well as for early detection and prevention efforts in
high-risk individuals.

O10.5 MINOR ALLELE OF RS2230912 IS
PROTECTIVE AGAINST RAPID CYCLING IN
A SWEDISH SAMPLE OF BIPOLAR DISORDER
PATIENTS
P. Nikamo* (1), L. Backlund (2), L. Frisén (3), I. Römer Ek
(2), L. Träskman-Bendz (4), H. Ågren (5), G. Edman (6), M.
Landén (2), U. Ösby (2), M. Schalling (1)
1. Neurogenetics Unit, Department of Molecular Medicine and
Surgery, Karolinska Institutet, Stockholm, Sweden 2.
Department of Clinical Neuroscience, Karolinska Institutet,
Stockholm, Sweden 3. Division of Psychiatry, Department of
Clinical Sciences, Karolinska Institutet, Danderyd University
Hospital, Stockholm, Sweden 4. Division of Psychiatry,
Department of Clinical Sciences, University Hospital, Lund,
Sweden 5. Academy at the University of Gothenburg,
Institution of Neuroscience and Physiology, Sweden
6. Department of Psychiatry, R&D Section, Danderyd
University Hospital, Sweden
* pernilla.nikamo@ki.se
Background: Bipolar disorder is a common and severe
psychiatric illness. Of bipolar patients, 15-20% suffers from
the rapid cycling subdiagnosis, defined by at least four
episodes of a mood disturbance during a twelve month period.
In previous studies the gene P2RX7 which is a purinergic
ATP-binding calcium channel expressed in neurons, has been
associated with bipolar disorder. Methods: We selected
three non-synonymous SNPs in the P2RX7 gene; RS7958311
(His270Arg), RS1718119 (Thr348Ala) and RS2230912
(Gln460Arg) as well as one synonymous SNP; RS1621388.
The RS2230912 polymorphism is non-conservative such that
the minor allele results in a glutamine to arginine change
(Gln460Arg), which is likely to affect P2RX7 dimerization
and protein–protein interactions. We performed an association
analysis of 646 Swedish patients, diagnosed with bipolar
disorder according to DSM-IV, comparing those with a rapid
cycling subdiagnosis (n=115) with those with other
subdiagnoses (n=375). Results: For the rapid cycling
subdiagnosis the RS2230912_G allele in the P2RX7 gene
showed a negative association (P=0.004; OR=0.46).
RS2230912 and RS1621388 are 367 bases apart and were
together as haplotype AT positively associated with rapid
cycling (P=0.01; OR=1.24) whereas the GT haplotype was
negatively associated (P=0.01; OR 0.49). Conclusion: In
Swedish bipolar patients with a rapid cycling subdiagnosis, we
identified in the P2RX7 gene two protective associations and
one association with an increased rate of rapid cycling. Thus,
our findings support previous findings of an association
between bipolar disorder and RS2230912_G allele in the
P2RX7 gene, although our findings were specifically related
to the rapid cycling subdiagnosis. Corresponding author:
O11 EARLY CAREER INVESTIGATOR
TRACK: WHOLE-GENOME APPROACHES
O11.1 ADDRESSING ALLELIC HETEROGENEITY IN
THE WHOLE-GENOME STUDY ERA: A
POPULATION-BASED LINKAGE STUDY
INVESTIGATING UNIPOLAR DEPRESSION
S. Cohen-Woods* (1), C. Lewis (1), M. NG (1), A. Butler (1),
K. Pirlo (1), A. Schosser (1), R. Uher (1), M. Owen (2), M.
Barnes (3), P. Muglia (4), M. Lathrop (3), S. Heath (3), K.
Aitchison (5), A. Farmer (1), I. Craig (1), P. McGuffin (1), G.
Breen (1)
1. MRC SGDP Centre, Institute of Psychiatry, King’s College
London 2. Department of Psychological Medicine, Cardiff
University 3. Centre National de Génotypage, 91057 Evry,
France 4. GSK Research & Development, Genetics, Drug
Discovery, Via Fleming 4, Verona, Italy and Greenford Road,
Greenford, Middlesex UB6 OHE, UK 5. Institute of
Psychiatry, King's College London
* sarah.cohen@kcl.ac.uk
Although the substantial genetic contribution to depression
predisposition is well-established, specific genes have failed to
be consistently identified through ‘traditional’ single-gene
association studies. Genome-wide association studies
(GWAS) have recently become viable through the
advancements in genotyping platforms and reduction in
chip-genotyping costs. A complementary strategy to the
standard case-control association analysis of genome-wide
association study (GWAS) data is population-based linkage
(PBL) analysis. PBL identifies relatively rare variants, as
opposed to common variants, and also accounts for the
possibility of allelic heterogeneity. Case samples from three
genetic studies in depression were combined; the Depression
Case-Control (DeCC) study, the Depression Network (DeNT)
study, and the Genome Based Therapeutic Drugs for
Depression (GENDEP) study. Controls screened by
questionnaire and/or telephone interview for absence of
psychiatric disorders, and lack of family history of psychiatric
disorders, were also genotyped. In total the sample presented
includes approximately 3,200 cases and 1,800 controls. Each
case individual was diagnosed with DSM-IV/ICD-10
depression, of at least moderate severity, as assessed by SCAN
interview. Samples were genotyped using the Illumina Human
610-quad DNA analysis bead chip. Loci showing evidence for
linkage will be presented, alongside a clear description of the
quality control applied. This represents the first clinical
case-control GWAS study applying population-based linkage
to date investigating recurrent unipolar depression. With
important and far-reaching implications for pharmaco-genetic
studies, more directed and economical research may be
applied to further elucidate the underlying aetiology, and
ultimately treatment, of unipolar depression.

O11.2 IMPROVEMENT OF PHENOTYPING IN
GENOME WIDE ASSOCIATION STUDIES ON
SCHIZOPHRENIA: AN APPLICATION OF FACTOR
ANALYSIS
E. Derks* (1), M. Boks (1), J. Allardyce (2), R. Ophoff (3), R.
Kahn (1), W. Cahn (1)
1. Department of Psychiatry, Rudolf Magnus Institute of
Neuroscience, University Medical Centre Utrecht, Utrecht,
The Netherlands 2. Psychiatry and Neuropsychology, School
for Mental Health and Neuroscience, EURON, SEARCH,
Maastricht University Medical Centre, Maastricht, The
Netherlands 3. Complex Genetics Section, Department of
Biomedical Genetics, University Medical Center Utrecht,
Utrecht, the Netherlands
* e.m.derks@umcutrecht.nl
Genetic factors explain a large proportion (81%) of the
variation in schizophrenia. Nevertheless, the identification of
specific genes is not very successful as the enormous
investments that are made on the genotypic level (e.g.,
genotyping ~1,000,000 SNPs) are not matched by similar
investments on the phenotypic level. We aim to improve the
assessment of individual differences in schizophrenia by
performing factor analysis on 66 Comprehensive Assessment
of Psychiatric History (CASH) symptoms in a sample of 2290
patients with schizophrenia, schizophreniform, schizoaffective
disorder, bipolar disorder or depression, and 1888 healthy
controls from the Netherlands. Variation in schizophrenia
symptoms is best represented by five latent dimensions
(positive, negative, mania, disorganisation, and depression).
Diagnostic subgroups show different patterns on the five latent
dimensions. Compared to healthy controls, patients diagnosed
with depression show elevated scores on each of the five
dimensions. Despite the fact that schizophrenia is a highly
heterogeneous disorder, gene finding studies collapse patients
with different symptom patterns into one group. However, if
in reality these patients have distinct genetic vulnerabilities,
this would dramatically decrease the statistical power to detect
functional genetic variants. Furthermore, case-control studies
on schizophrenia should exclude patients diagnosed with
depression as healthy controls. Even though these patients do
not meet diagnostic criteria for schizophrenia, they obtain high
scores on the five latent dimensions which explain variation in
schizophrenia symptoms suggesting that they share part of the
genetic vulnerability to schizophrenia. We recommend using
continuously distributed factor scores as quantitative outcome
measures in future gene finding studies.
O11.3 HIGH COVERAGE WHOLE-GENOME
SEQUENCING IN SCHIZOPHRENIA: PROOF OF
FEASIBILITY AND VARIANT ANNOTATION
PROTOCOLS
A. Need* (1), D. Ge (1), K. Shianna (1), J. Thrall (2), J. Maia
(1), J. McEvoy (2), D. Goldstein (1)
1. Institute for Genome Sciences & Policy, Duke University,
Durham, NC 27710, USA 2. Department of Psychiatry and
Behavioral Sciences, Duke University Medical Center,
Durham, NC 27509, USA
* need0001@duke.edu
Large-scale genome-wide association studies have suggested
that common genetic variants make at most a modest
contribution to the high heritability of schizophrenia. These
findings, together with the association with schizophrenia of a
number of rare copy number variants, have led to the
hypothesis that the much of the heritability may be explained
by rare variants with strong effects. In order to
comprehensively screen for such variation it is necessary to
sequence entire patient genomes (or exomes). Here we present
the first whole genome sequence of a patient with
schizophrenia, generated as part of a larger schizophrenia
sequencing study at the Center for Human Genome Variation
at Duke University. We use these data to illustrate the
procedures involved in generating and analyzing
whole-genome sequence data in an academic setting. We
present a novel software program, called Sequence Variant
Analyzer, which is used to annotate and assign function to
variants identified from the sequence data. We will report the
total number of novel coding variants and their predicted
function (nonsense, missense, synonymous, splice-affecting,
etc), as well as detailed analyses of candidate genes, regions
and pathways that have been associated with schizophrenia
though family studies or animal models. Collectively, these
analyses confirm the feasibility of whole-genome sequencing
as a discovery tool in psychiatric genomics.

O11.4 GENETICS OF ALCOHOL DEPENDENCE
COMORBIDITY IN BIPOLAR DISORDER:
GENOME-WIDE ASSOCIATION STUDY
E. Nwulia* (1), M. Hipolito (1), W. Lawson (1), P. Zandi (2),
J. Nurnberger Jr (3), Bipolar Genome Study (BiGS)
1. Howard University 2. Johns Hopkins University 3.
University of Indiana
* enwulia@howard.edu
The identification of bipolar disorder (BD) susceptibility
genes has been hindered by genetic heterogeneity , among
other factors. Genetic heterogeneity may be a reflection of
phenotypic variability. Several lines of inquiry have suggested
that genetic predisposition to BD might also be expressed as
liability to alcohol dependence (AD) in subgroups of families.
To further explore this relationship, we performed a
Genomewide Association Study (GWAS) for comorbid AD in
a sample of unrelated BD individuals (n=1001) of European
ancestry (EA) recruited from 11 US institutions as part of the
NIMH Collaborative Genetics of Bipolar Disease Study. BD
cases were classified into those with AD (BDAD, N = 460)
and those without AD (BDNAD, n = 528) for the purpose of
case-only GWA. Genotyping using Affymetrix 6.0 array was
provided by the Genetic Analysis Information Network
(GAIN). Analyses involved logistic and polytomous
regressions; we also adjusted for sex, which was significantly
associated with alcohol dependence (51.2% in males versus
41.9% in females; P = 0.003). The strongest statistical signal
(OR, 1.64; P = 1.19 x 10-6) from this case-only analysis was
found in the WDR59 gene on chromosome 16q23.1. We also
found strong association between a SNP in the alphaN-catenin
(CTNNA2) gene on 2p12 with BDAD vs. BDNAD (OR, 1.51;
P < 7.0 x 10-6). The risk allele for this locus was however
inversely associated with BDNAD vs. normal controls (NC)
(OR, 0.77;P < 10-3), but not with BDAD vs. NC (OR, 1.16; P
< 0.08). Confirmation of these putative associations,
coherence with other lines of study, and demonstration of
biological plausibility are needed for causal inferences to be
applied to these findings.
O11.5 GENE BASED AND PATHWAY ANALYSIS
REVEAL GENOME-WIDE SIGNIFICANT GENES AND
MOLECULAR PATHWAYS ASSOCIATED WITH
BIPOLAR DISORDER
I. Pedroso* (1), D. Collier (2), A. Farmer (1), P. McGuffin
(1), G. Breen (1)
1. MRC SGDP Centre, Institute of Psychiatry, King’s College
London, De Crespigny Park, London SE5 8AF, UK 2.
Division of Psychological Medicine, Institute of Psychiatry,
King’s College London, De Crespigny Park, London SE5
8AF, UK
* intipedroso@gmail.com
Despite the high heritability (~80%) and familial aggregation
observed in Bipolar Disorder (BD), its molecular genetic
underpinnings are still largely unknown. Candidate gene
findings have yielded few replicated associations. Data is now
available from several Genome Wide Association Scans
(GWAS) of BD. We reanalyzed four of these GWAS using
gene based and pathway analysis. We combined the
association statistics of SNPs on a gene-wide basis while
correcting by the number of tests and the correlation between
them (i.e. LD between SNPs). Our method has advantages
over alternatives: it is neither biased by the gene-size nor
inflated by the correlation between the tests, it allows the use
of summary statistics and LD information from HapMap and it
is computationally inexpensive. We identified several
genome-wide significant genes, which were below multiple
testing correction on the single SNP analysis, and several
pathways passed multiple testing correction. Our results
suggest that combining the effect of genetic variants enhance
the power to detect genetic associations and provide replicated
evidence for common genetic variation on genes and
biological processes on the aetiology of BD.

O11.6 A GENOME-WIDE ASSOCIATION STUDY OF
OBSESSIVE-COMPULSIVE DISORDER USING DNA
POOLING
J. Wendland* (1), F. McMahon (1), D. Denys (2), S. Walitza
(3), M. Arcos-Burgos (4), S. Cichon (5), T. Schulze (6), M.
Rietschel (6), D. Murphy (1)
1. NIMH 2. Univ. of Amsterdam 3. Univ. of Zurich 4. Univ.
of Miami 5. University of Bonn 6. Central Institute of Mental
Health, Mannheim
* wendlandj@mail.nih.gov
Obsessive-compulsive disorder (OCD) is a severe
neuropsychiatric illness characterized by persistent, intrusive
thoughts and repetitive behaviors. There is compelling
evidence for major genetic contributions to the etiology of
OCD from twin and family studies. The exact molecular
mechanisms, however, are not fully elucidated, and few genes
or polymorphisms have been consistently replicated in genetic
studies. Here, we used a genome-wide association study
approach to identify common genetic variants involved in
OCD. We pooled equimolar amounts of 40 – 60 unrelated
individuals’ genomic DNA and used Illumina single
nucleotide polymorphism (SNP) microarray chips
interrogating over 320,000 markers distributed across the
genome. We tested 4 OCD pools derived from US probands
and 4 OCD pools from Dutch probands and an equal number
of ethnically and geographically matched control pools.
Inferred allele frequencies between case and control pools
were compared with a two-sided t test. We identified 25 SNPs
that were nominally significantly associated at P < .01 in both
the US and European case-control comparison and had the
same direction of effect. One of these markers, rs1409294,
was replicated in an independent collection of 103 German
early-onset OCD trios which were individually genotyped by
5’ exonuclease methodology. The replicated variant is located
on chromosome 6q22.31 in an intergenic region between the
non-coding RNA gene STL (six-twelve leukemia) and
NKAIN2, a protein-coding gene expressed in the brain. In
addition to further replication attempts, functional studies are
now warranted to determine the biological mechanisms
through which the newly-identified locus may be relevant to
OCD etiology.
O12 SCHIZOPHRENIA 3
O12.1 FOLLOW-UP FINE MAPPING AND DEEP
RE-SEQUENCING OF ZNF804A IN SCHIZOPHRENIA.
H. Williams (1), N. Norton (1), S. Dwyer (1), L. Carroll (1),
L. Georgieva (1), T. Peirce (1), V. Moskvina (1), M.
Hamshere (1), I. Nikolov (1), P. Holmans (1), S. Zammit (1),
A. Hartmann (2), H. Moller (2), D. Morris (3), E. Quinn (3),
N. Williams (1), I. Giegling (2), N. Craddock (1), M. Gill (3),
A. Corvin (3), D. Rujescu (2), G. Kirov (1), M. Owen (1), M.
O'Donovan (1)
1. Cardiff University 2. Ludwig-Maximilians-University 3.
Trinity College Dublin
The use of genome wide association studies (GWAS) to
uncover genetic variants that are robustly associated with
complex diseases is well established. However, further work is
required to identify which genetic variant or variants actually
confer disease risk and the mechanism involved. We have
previously published the results of a schizophrenia GWAS
(O’Donovan, et al 2008) where an intronic SNP (rs1344706)
in the gene ZNF804A was our most significant finding (meta
P=1.61x10-7). Here we describe follow-up studies aimed at a)
confirming the evidence for robust association obtained in our
and c) determining how this might confer risk to the disorder.
We have performed a meta analysis including additional data
from recently published schizophrenia GWAS and show that
marker rs1344706 now exceeds genome wide levels of
significance. We performed mutation screening of all coding
sequence, association analysis of functional and tag SNPs as
well as deep re-sequencing of the genomic region around
ZNF804A. Our results show that although we have
discovered and characterised many new novel polymorphisms,
rs1344706 is still the most significant variant at this locus.
Finally using the GeneVar database we shown that the
rs1344706 risk allele (T) is associated with an over expression
of the ZNF804A transcript.

O12.2 SCHIZOPHRENIA-RELATED BEHAVIORAL
CHANGES IN G72/G30 TRANSGENIC MICE
D. Otte* (1), A. Bilkei-Gorzo (1), Ö. Yilmaz (1), C. Turck
(2), M. Holst (3), K. Schilling (4), R. Abou Jamra (5), P.
Propping (5), A. Zimmer (1)
1. Department of Molecular Psychiatry, University of Bonn,
Germany 2. MPI Psychiatry, Munich, Germany 3. Institute of
Anatomy, University of Bonn, Germany 4. Institute of
Anatomy, University of Bonn, Germany 5. Institute of Human
Genetics, University of Bonn, Germany
* d.otte@uni-bonn.de
Genetic studies have implicated the evolutionary novel,
anthropoid primates-specific gene locus G72/G30 in
psychiatric diseases like schizophrenia, bipolar- and
panic-disorders. It encodes for a protein LG72 that has been
controversially discussed as putative activator or inhibitor of
the peroxisomal enzyme D-amino-acid-oxidase (DAO), or as a
mitochondrial protein. Here we have generated “humanized”
BAC transgenic mice (G72Tg) that express G72/G30
transcripts. In-situ hybridization analysis revealed that G72
mRNAs are prominently expressed in granular cells
throughout the brain. Transgenic mice show a number of
behavioral phenotypes that are relevant to psychiatric
disorders. These phenotypes include deficits in sensorimotor
gating, locomotor deficits, increase compulsive behaviors and
deficits in smelling. These results identify LG72 as a possible
key protein in pathomechanism of psychiatric diseases.
O12.3 DEEP RESEQUENCING AND ASSOCIATION
ANALYSIS OF SCHIZOPHRENIA CANDIDATE
GENES
P. Sullivan (1), J. Crowley* (1), M. Morgan (2), P. Sklar (3),
S. Purcell (4), J. Lieberman (5), R. Gibbs (2)
1. UNC Chapel Hill 2. Baylor College of Medicine 3.
Massachusetts General Hospital 4. The Broad Institute 5.
Columbia University
* crowley@unc.edu
In 2006, there were ~10 genes for which there was reasonable
evidence for involvement in the etiology of schizophrenia. The
pattern of results for these genes suggests that there may be
sequence variants that have not yet been discovered, and
existing re-sequencing has been limited. To address this
limitation, we re-sequenced the coding regions, 5’ and 3’
UTRs, splice sites, promoters and conserved intronic regions
of these 10 genes in 727 cases with schizophrenia from the
CATIE clinical trial and 729 matched controls. A total of 778
single nucleotide polymorphisms (SNPs) were identified by
resequencing, including 620 novel variants. A total of 30 high
priority variants were deemed worthy of genotyping in a larger
population, based on a combination of factors including:
association with schizophrenia in CATIE, novelty, SNP type
(non-sense and missense mutations) and minor allele
frequency in cases of European ancestry. These 30 variants are
currently being examined for association with schizophrenia in
a distinct sample of 3,391 schizophrenia cases and 3,181
controls, all of European ancestry and collected by the
International Schizophrenia Consortium (ISC). In conclusion,
schizophrenia candidate genes possess a great deal of common
and rare variation not covered on current genome-wide
association platforms. Further analysis of these variants in
distinct schizophrenia samples will provide a clearer picture of
the role these genes play in schizophrenia etiology.

O12.4 FINE MAPPING OF AHI1 ON 6Q23 AS A
SUSCEPTIBILITY GENE FOR SCHIZOPHRENIA
FROM ASSOCIATION TO EVOLUTIONARY
EVIDENCES
F. Torri (1), A. Akelai (2), S. Lupoli (3), M. Sironi (4), M.
Fumagalli (4), E. Osimo (1), C. Dal Fiume (1), D. ,
Amann-Zalcenstein (5), E. Ben-Asher (5), K. Kanyas (2), R.
Cagliani (4), D. Lancet (5), P. Cozzi (6), L. , SStrik Lievers
(1), E. Salvi (1), A. Orro (7), J. Beckmann (8), B. Lerer (9), F.
Macciardi (10)
1. University of Milan, Filarete Foundation, Milan, Italy
2. Hadassah–Hebrew University Medical Center, Jerusalem,
Israel 3. INSPE, Scientific Institute San Raffaele, Milan, Italy
4. Scientific Institute IRCCS E. Medea, Parini (LC), Italy 5.
Weizmann Institute of Science, Rehovot, Israel 6. ITB, CNR,
Milan, Italy 7. ITB, CNR, Milan, Italy;CILEA Consortium,
Segrate, Milan, Italy 8. Centre Hospitalier Universitaire
Vaudois and University of Lausanne, Switzerland 9.
Hadassah–Hebrew University Medical Center, Jerusalem,
Israel;Miller School of Medicine, University of Miami
10. University of Milan, Filarete Foundation, Milan,
Italy;Department of Psychiatry and Human Behavior,
University of California, Irvine, CA, USA
In previous linkage studies we identified a susceptibility
region on 6q23.3 in a set of Arab-Israeli families. In a
follow-up study we proposed the Abelson Helper Integration
Site 1 (AHI1), which plays a key role in neurodevelopment, as
a gene associated with SCZ. To definitively confirm AHI1 as
the best finding in the region, we performed a dense mapping
genotyping 2019 SNPs in 58 families of the previously studied
sample. Our strongest associated SNPs and haplotypes lay
within a 500 kb genomic region (135.6–136.1 Mb)
encompassing AHI1 and BC040979. Within the AHI1 gene,
rs11154801 (p=6.23E-06) and rs7759971 (p=1.84E-06)
showed the strongest associations, with haplotypes having
p-values in the 10E-8 to 10E-10 range. The second most
highly significant region maps immediately distally from
AHI1 and includes the intergenic region between BC040979
and PDE7B, and both the PDE7B and MAP7 genes, which
show brain expression. Given a possible involvement of
positive selection of SCZ genes we resequenced a 10kb region
within AHI1 in ethnically defined populations and found
evidence for a selective sweep in Europeans. Network analysis
indicated the presence of two haplotype clades, with
SCZ-susceptibility haplotypes clustering within the major
clade. In line with new wave of genetic investigations
focusing now on the implication of rare and common copy
number variants (CNVs) in SCZ, we have also carried out a
whole-genome CNV analysis in the same Arab-Israeli sample
detect CNVs investigate the pathways in which the
SCZ-associated CNVs are mainly involved to build a potential
model of interaction with the SCZ-associated genes we found
in our study. Our data confirm and definitely support the role
of AHI1 as a susceptibility gene for SCZ.
O12.5 COPY NUMBER VARIANTS AFFECTING
MYELIN GENES IN SCHIZOPHRENIA
L. Georgieva* (1), G. Kirov (1), P. Holmans (1), V.
Moskvina (1), V. Haroutunian (2), T. Sakurai (1), J. Young
(3), J. Buxbaum (3), N. Craddock (1), M. Owen (1), M.
O'Donovan (1)
1. MRC Centre for Neuropsychiatric Genetics and Genomics,
Department of Psychological Medicine, Cardiff University,
Heath Park, Cardiff, United Kingdom 2. Department of
Psychiatry, Mount Sinai School of Medicine, New York,
USA;Mental Illness Research, Education and Clinical Centres,
Bronx Veterans Affairs Medical Centre, Bronx, New York,
USA 3. Department of Psychiatry, Mount Sinai School of
Medicine, New York, USA
* georgievaln@cardiff.ac.uk
Background: Abnormal oligodendrocyte function and
myelination have been implicated in schizophrenia (SZ) by a
diverse range of experimental approaches including gene
expression analysis, neuropathology, neuroimaging and
genetic association. Some of the most convincing findings in
SZ genetics in the last 18 months concern the involvement of
low frequency copy number variants (CNVs) in that disorder.
Aims: To assess whether rare CNVs (

O13 AUTISM
O13.1 ALTERED SYNAPTIC PLASTICITY IN MICE
LACKING ONE COPY OF THE SHANK3 GENE, A
GENE MUTATED IN AUTISM SPECTRUM
DISORDERS
J. Buxbaum* (1), T. Sakurai (1), X. Wang (1), Q. Zhou (1),
D. Papapetrou (1), P. Hof (1), O. Bozdagi (1), L. Ospina (1)
1. Mount Sinai School of Medicine
* joseph.buxbaum@mssm.edu
Background: Studies have demonstrated that rare, highly
penetrant genetic variants can lead to autism spectrum
disorders (ASDs). With the identification of genes
contributing to the development of ASD we are in a position
to develop animal models to understand the developmental
consequences of alterations in these genes. One recurrent
finding is that loss of one copy of SHANK3, either by copy
number variation (CNV) or by mutation, leads to global
developmental delay, frequently with an ASD. Methods: We
have used gene-targeting methods to disrupt Shank3 in mice
and have characterized these mice from biochemical,
electrophysiological, neuropathological and behavioral
standpoints. Results: Mice lacking one copy of Shank3
develop normally and are born with Mendelian ratios.
Developmental milestones are normal in the heterozygotes as
determined by detailed observation and behavioral testing.
The frequency of miniature excitatory postsynaptic currents is
reduced in these mice indicating a deficit in spontaneous
neurotransmitter release. Moreover, hippocampal long-term
potentiation (LTP) is deficient, while long-term depression
(LTD) is unchanged. Microscopic examination of synaptic
spines demonstrates that the normal, stable modulation of
spine volume in response to LTP is not present in the
heterozygous animals, although transient changes are detected
Discussion: Our analyses support a role for abnormal synaptic
development and function in at least some forms of ASDs.
These studies lead to direct predictions in human studies and
to potential new avenues for ASD therapeutics.
O13.2 NARROWING THE CRITICAL DELETION
REGION FOR AUTISM SPECTRUM DISORDERS IN
CHROMOSOME 16P11.2
A. Crepel* (1), W. De La Marche (2), J. Fryns (1), I. Noens
(3), J. Steyaert (2), K. Devriendt (1), H. Peeters (1)
1. Center for Human Genetics, University Hospital Leuven,
Leuven, Belgium 2. Department for Child and Youth
Psychiatry, University of Leuven, Leuven, Belgium
3. Center for Parenting, Child Welfare and Disabilities,
Department of Educational Sciences, University of Leuven,
Leuven, Belgium
* an.crepel@med.kuleuven.be
One of the most common genomic disorders associated to
autism to date is a ~600kb deletion containing 25 genes at
chromosome 16p11.2. It was reported to occur in up to 1% of
autistic patients in 3 large autism studies and was recently
studied in MR/MCA patients, extending the phenotype to
other developmental disorders and speech disorders. The
inheritance pattern is similar to that of other major effect
variants implicated in complex disorders: the deletion is not
limited to sporadic patients with de novo mutations, but may
be inherited from unaffected parents. This microdeletion is
typically ~600kb in size and flanked by segmental
duplications, which explains its recurrent nature. Of the 25
genes in this region, many represent good autism candidate
genes based on expression profiles, pathway analysis and
other available functional data. Although no firm association
has been established for any one of these genes, mutation
studies yielded suggestive evidence for the SEZ6L2 gene.
We report the discovery of a smaller, 115kb deletion within
the known 16p11.2 CNV in a 3 generation family with
4 patients with autism and normal intelligence. Segregation
was studied by independent psychiatric evaluation and
collecting scores on the Social Responsiveness Scale (SRS) in
9 family members. From these data we have evidence for
segregation of the small deletion with autism or autistic traits
in this family. We conclude that this observation narrows the
critical deletion region for autism on chromosome 16p11.2 to
only 5 genes.

O13.3 GENETIC MAPPING OF TEMPORAL MEMORY
COMPONENTS IN MICE REVEALS A
HOMOLOGOUS AUTISM LOCUS
H. Bruining (1), O. Stiedl (2), F. Meye (1), E. Pjetri (1), H.
Oppelaar (1), L. Nonkens (1), G. Ramakers (1), C. Fernandez
(3), H. Swaab (4), H. van Lith (5), H. van Engeland (1), M.
Kas (5)
1. Rudolf Magnus Institute of Neurosciences, Department of
Psychiatry, University Medical Centre Utrecht, the
Netherlands 2. Center for Neurogenomics and Cognitive
Research, Neuroscience Campus Amsterdam, VU
University Amsterdam, The Netherlands 3. Social, Genetic
and Developmental Psychiatry Centre, Institute of Psychiatry,
King's College London, London, United Kingdom
4. University of Leiden, Department of Social Sciences, The
Netherlands 5. Rudolf Magnus Institute of Neurosciences,
Department of Neuroscience and Pharmacology University
Medical Centre Utrecht, The Netherlands
Chromosome substitution strains (CSSs) of mice are
extremely useful to identify genetic factors underlying
neurobiological mechanisms of complex behaviors. The
current study mapped chromosomes affecting the regulation of
memory formation in a social discrimination (SD) task in 21
strains of the CSS panel (C57BL/6J-Chr#A/NaJ). Selected
CSSs with altered SD performance were tested in various
hippocampus-dependent learning tasks, and long-term
potentiation (LTP) was assessed as a measure of hippocampal
plasticity. We identified particular CSSs with either
impairment in short-term or long-term SD performance. For
example, one CSS was unable to discriminate conspecifics at
5-min training-test interval (TTI), but showed SD at 24 hr
TTI. In contrast, another CSS showed SD after 5 min, but not
after a TTI of 24 hr. These CSS-specific temporal
performance differences were confirmed in object
discrimination and fear conditioning. No differences were
found in the Morris water maze when compared to C57BL/6J
controls, indicating that spatial memory was not affected.
Electrophysiological measurements in the hippocampus
revealed an elevated threshold for LTP induction only in the
CSS with long-term memory impairments. These findings
indicate that temporal processes of memory formation can be
dissected at the genetic, behavioral and electrophysiological
level. Additional phenotypic characterization of specific
performance differences (e.g., encoding and extinction of
memory) indicates a common genetic contribution of
short-term versus long-term memory components in both
social and non-social discrimination capacity and fear
conditioning. Interestingly, subsequent genetic mapping of
these social and non-social memory phenotypes revealed a
mouse QTL-interval homologous to an autism CNV locus.
O13.4 DISSECTING THE CLINICAL
HETEROGENEITY OF AUTISM SPECTRUM
DISORDERS THROUGH DEFINED GENOTYPES.
H. Bruining (1), L. de Sonneville (2), H. Swaab (2), M. de
Jonge (1), M. Kas (3), H. van Engeland (1), J. Vorstman (1)
1. Rudolf Magnus Institute of Neuroscience, Department of
Children and Adolescent Psychiatry,
University Medical Centre Utrecht, the Netherlands 2.
Institute of Social Sciences, Department of Developmental
disorders, University of Leiden, the Netherlands 3. Rudolf
Magnus Institute of Neuroscience, Department of
Neuroscience and Pharmacology, University Medical Centre
Utrecht, Utrecht, the Netherlands
The increasing evidence for a causative role of genetic
variants with large effect in autism spectrum disorders (ASD)
raises the question whether specific genetic subtypes lead to
ASD phenotypes that are distinguishable from the remainder
of the ASD population. We examined autistic symptoms in
two samples with a genetic variant previously shown to cause
ASD: patients with the 22q11.2 deletion (22q11DS) or with
Klinefelter syndrome (KS). These assessments aim to provide
proof-of-concept of the existence of genotype-specific ASD
phenotypes. ASD symptom profiles in 22q11DS (n=90) and
KS (n=51) were statistically compared at two different levels:
1) with a large group of idiopathic ASD patients (n=371) and
2) with the non-ASD subjects among the 22q11DS and KS
groups. Discriminant analyses of the autistic symptom profiles
clearly showed that autistic phenotypes in the two subgroups
could be delineated from the idiopathic ASD. Furthermore, the
two subgroups (22q11DS and KS) displayed enhanced
symptom homogeneity compared to the idiopathic ASD
patients.To our knowledge, this is the first reversed
phenotyping approach that provides robust evidence for the
existence of genetic subtype-specific ASD phenotypes within
the ASD population. We propose that evidence for the
existence of a phenotype related to a specific genetic variant is
provided when 1) the ASD phenotypes of a genetic subtype
can be delineated from the remainder of the ASD population
based on ASD symptomatology, and 2) the variance of ASD
symptoms within a genetic subtype is significantly smaller in
comparison to the variance of the remainder of the ASD
population.

O13.5 THE EFFECT OF CHR16P11.2
MICRODELETIONS AND MICRODUPLICATIONS
ON GENE EXPRESSION IN AUTISM SPECTRUM
DISORDERS AND SCHIZOPHRENIA
M. Kusenda, V. Vacic , S. Yoon, J. Sebat
* Kusenda@cshl.edu
The number of rare variants found to be associated with
multiple psychiatric disorders is growing. One such locus is a
recurrent ~600kb copy number variant (CNV) at 16p11.2,
occurring in approximately 1% of autism and 0.3% of
schizophrenia cases, as compared to 0.01% of the general
population. We hypothesize that one or more of the 25 genes
at this locus contribute to the neurodevelopmental phenotype
observed in patients with psychiatric disorders. To determine
how gene function is altered by this CNV, we analyzed
genome wide expression data from Epstein Barr Virus (EBV)
transformed Lymphoblast cell lines (LCL), of patients with
autism or schizophrenia who have a de novo or inherited
16p11.2. Using RNA expression profiling by Affymetrix
Human Genome U133 Plus 2.0 chip, we examined differential
cis and trans gene expression in individuals with 1, 2, or 3
copies of the genomic region (6, 19, 16 respectively). Our
results highlighted 140 genes located both within and outside
of the mutation which expression correlates with genotype.
Some of these genes play a role in development while others
have been associated with psychiatric disorders. We are
currently analyzing our list of 140 dysregulated genes to
identify pathways and functions relevant to
neurodevelopment, and psychiatric disorders. Data generated
by this study will give insight into dosage sensitive genes
within the risk variant, and may help pinpoint genes which are
relevant to pathology of the psychiatric disorders associated
with this region.
O14 EPIGENETICS
O14.1 INVESTIGATING GENOME-WIDE
EPIGENETIC DIFFERENCES IN TWINS
DISCORDANT FOR ALCOHOL DEPENDENCE
C. Nymberg* (1), A. Lourdusamy (1), J. Mill (1), S.
Desrivieres (1), R. Rose (2), J. Kaprio (3), D. Dick (4), G.
Schumann (5)
1. Social, Genetic and Developmental Psychiatry Centre 2.
University of Indiana 3. University of Helsinki 4. Virginia
Institute for Psychiatric and Behavioral Genetics 5. Social,
Genetic and Developmental Psychiatry Centre
* charlotte.nymberg@kcl.ac.uk
Alcohol dependence (AD) is the result of interacting
environmental and genetic factors. However, to date
researchers have been unable to identify specific causal
genetic or environmental risk factors underlying the disorder.
Recent studies suggest that DNA methylation, or the silencing
of gene expression, may play an important role for
understanding psychiatric disorders such as AD. At least two
factors influence DNA methylation: 1) environmental factors
may produce epigenetic marks which speed up the process of
adaptation to a changing and less predictable environment; 2)
genes may encode enzymes and proteins that help construct
and maintain methylation-patterns. To control for the genetic
components underlying DNA methylation, the current study
adopted a twin design. The study aims to investigate DNA
methylation patterns in blood samples from 36 monozygotic
twins, diagnostically discordant for AD. To date psychiatric
research has mainly taken a candidate gene approach to the
investigation of DNA methylation. However, this focus may
be too constrained. This study takes a genome-wide approach
to investigating DNA methylation using a methylation
sensitive array with 385.000 features covering promoter
regions and CpG islands. Although the results are preliminary,
they suggest that methylation differences related to psychiatric
disorders such as alcohol dependence are worthy of further
study.

O14.3 IDENTIFICATION OF IMPRINTED GENES
CONTRIBUTING TO SPECIFIC BRAIN REGIONS
USING HIGH THROUGHPUT SEQUENCING
C. Barr (1), K. Wigg (1), E. Dempster (1), L. Gomez (1), Y.
Feng (1), P. Monnier (1), R. Logan (1), J. Eubank (1)
1. The Toronto Western Research Institute
Current estimates suggest that there are around 100 imprinted
genes, but this number may be as high as 600, with some
imprinted in a tissue/cell type specific pattern and little is
known of these genes. We followed up evidence that suggests
imprinted genes influence the development of specific brain
regions. We predicted that key genes expressed from the
paternal genome will contribute to the development of the
hypothalamus while key maternally expressed genes will
influence the development of the neocortex. We developed a
strategy using crosses and reverse crosses of mouse strains to
determine the parent-of-origin of expressed genes. We used
next generation sequencing of mRNA tags from the cortex and
the thalamus/hypothalamus dissected from the F1 to identity
tags differing in expression between the crosses. We
identified tags that were differentially expressed between the
crosses showing the same pattern of parent-of-origin effect in
both brain regions including known imprinted genes (Meg3,
Snrpn, Rian) and genes with no prior evidence for
parent-of-origin effects (Pctk3, Klf10). We also observed
genes that displayed a parent of origin effect in only one brain
region with biallelic expression in the other region (Pon2,
Itgb1bp1). Our results show the feasibility of using next
generation sequencing of RNA as a genome-wide approach to
identify novel imprinted genes as well as to identify tissue
specific effects. The understanding of parent-of-origin effects
in specific brain regions will make a significant contribution to
our understanding of the role of imprinting in brain
development and function.
O14.4 EPIGENETIC DYSREGULATION OF HTR2A IN
POST-MORTEM BRAIN OF PATIENTS WITH
SCHIZOPHRENIA AND BIPOLAR DISORDER
H. Mostafavi-Abdolmaleky (1), S. Yaqubi (2), P.
Papageorgis (2), S. Thiagalingam (3)
1. Boston University, Department of Medicine and Iran
University of Medical Sciences, Department of Psychiatry &
Mental Health Research Center 2. Boston University,
Department of Medicine, Genetics Programs 3. Boston
University, Department of Medicine
Introduction: Pharmacologic and genetic studies provided
evidence for the involvement of HTR2A in schizophrenia
(SCZ) and bipolar disorder (BD) pathogenesis. However,
HTR2A polymorphisms have minimal effect in the
pathogenesis of these diseases. Hypothesizing that epigenetic
dysregulation of 5HTR2A may have a role in SCZ and BD we
analyzed promoter DNA methylation of HTR2A in
post-mortem brains. Method:DNA derived from dorsolateral
frontal cortex of patients with SCZ and BD and normal
controls (each 35) obtained from the Stanley Medical
Research Institute. HTR2A polymorphisms was determined
using enzymatic restriction of PCR product. qRT-PCR was
used to quantify gene expression level and bisulfite
sequencing to assess DNA methylation level of CpGs at
HTR2A promoter. Results: We found strong evidence for: 1)
epigenetic fine tuning of HTR2A; 2) inverse correlation
between promoter DNA methylation and gene expression
levels; 3) higher expression of HTR2A in individuals carrying
the G allele of -1438A/G polymorphism; 4) hypo-expression
of HTR2A in SCZ; 5) DNA hypermethylation of cytosine
located before -1438A/G polymorphic site (determined in
individuals with the GG genotype) in SCZ and BD versus the
controls; 6) correlation between methylation level of this
cytosine and neighboring cytosines followed by guanine and
several other cytosines followed by adenine which their
methylation levels are inversely correlated with gene
expression level. Conclusion: Aberrant DNA methylation of
CpG and CpA sites of the HTR2A promoter region may
contribute to SCZ and BD pathogenesis, particularly in
individuals carrying the G allele of -1438A/G polymorphism.

O14.5 ALLELIC SKEWING OF DNA METHYLATION
IS WIDESPREAD ACROSS THE GENOME
L. Schalkwyk (1), E. Meaburn (1), R. Smith (1), E. Dempster
(1), R. Plomin (1), J. Mill* (1)
1. Institute of Psychiatry, King's College London
* j.mill@iop.kcl.ac.uk
DNA methylation is a key epigenetic mechanism involved in
the developmental regulation of gene expression. Across the
majority of the genome, DNA methylation is assumed to be
complementary on both alleles, although there are several
exceptions, most notably in regions subject to genomic
imprinting. Although mounting evidence supports the notion
that differential allelic expression is widespread, the full extent
of allele-specific DNA methylation (ASM) in the human
genome has not been assessed. We present the first large-scale
survey of the degree of allelic skewing of DNA methylation
with the aim of identifying novel differentially methylated
regions (DMRs) associated with either genomic imprinting or
DNA sequence variation. We used high-resolution
microarrays to quantitatively assess changes in normalized
relative allele signals (RAS) for single nucleotide
polymorphisms (SNPs) in amplicons covering 7.6% of the
human genome following cleavage with a cocktail of
methylation-sensitive restriction enzymes (MSREs). Our
approach detected clear examples of ASM in the vicinity of
known imprinted loci, highlighting the validity of the method,
and selected findings were independently verified using
bisulfite-mapping and gene expression analyses. In total 2,705
(1.5%) of our informative SNPs demonstrated an average RAS
change >0.10 following MSRE digestion. These data suggest
that >35,000 such sites exist across the genome, and that some
degree of ASM is a widespread phenomenon.
O15 GENE ENVIRONMENT
INTERACTIONS
O15.1 THE INTERACTION OF VARIATIONS IN THE
FKBP5 GENE AND ADVERSE LIFE EVENTS IN
PREDICTING THE FIRST ONSET OF DEPRESSION
DURING A TEN-YEAR FOLLOW-UP
P. Zimmermann* (1), T. Brueckl (1), H. Pfister (1), E.
Binder (1), M. Uhr (1), R. Lieb (2), F. Holsboer (1), M. Ising
(1)
1. Max Planck Institute of Psychiatry, Germany 2. University
of Basel, Switzerland
* pzimmer@mpipsykl.mpg.de
Background: The co-chaperone FKBP5 of hsp-90 is an
important modulator of glucocorticoid receptor (GR) function,
the main receptor of the stress hormone system. By
modulating this system, FKBP5 is in a key position to
modulate gene-environment interactions (GxE) critical for the
pathogenesis of major depression. In fact, associations
between single nucleotide polymorphisms (SNPs) in the
FKBP5 gene and susceptibility to mood disorders as well as
interaction with early trauma to predict post traumatic stress
disorder (PTSD) have been reported (Binder et al., 2004;
2008). Aim:To explore GxE between variations in the FKBP5
gene and adverse (separation and traumatic) events in
predicting the first onset of a major depressive episode (MDE)
in a ten-years prospective-longitudinal community survey.
Methods:Analyses are based on 884 Caucasians (14-24 years
at baseline) without baseline MDE who completed the
ten-year follow-up. Data were assessed with the M-CIDI
according to its DSM-IV algorithms. Five SNPs within the
FKBP5 gene were selected for genotyping according to the
results of previous studies (Binder et al., 2004, 2008; Ising et
al., 2008). Results:While we did not observe genetic main
effects, we found interactions between the five SNPs and
traumatic (but not separation) events with the strongest effect
for severe trauma (pcorrected: 1.8x10-3 to

O15.2 INTERACTION BETWEEN CHILDHOOD
ADVERSITY AND COMT VAL158MET
POLYMORPHISM IN PSYCHOTIC DISORDER
H. Fisher* (1), C. Morgan (1), S. Luzi (1), M. Di Forti (1), P.
Dazzan (1), C. Pariante (1), D. Collier (1), K. Aitchison (1), A.
David (1), R. Murray (1), P. McGuffin (1)
1. Institute of Psychiatry, King's College London
* helen.fisher@iop.kcl.ac.uk
Childhood adversity has frequently been associated with
psychosis but not all exposed individuals develop this disorder
suggesting that some may have a genetic vulnerability. The
valine (Val) allele of the catechol-O-methyltransferase
(COMT) Val158Met polymorphism has been linked to
psychosis in those exposed to stress in adulthood. Therefore,
we predicted this allele would also interact with childhood
adversity in the development of clinically-relevant psychotic
disorders. In a cross-sectional study, 161 first-presentation
psychosis patients and 100 unaffected controls completed the
Childhood Experience of Care and Abuse Questionnaire
(CECA.Q) to determine experience of at least one adverse
event before 17 years of age (physical or sexual abuse,
parental separation or death, taken into care, disrupted living
arrangements). Blood samples were genotyped for the COMT
Val158Met polymorphism using polymerase chain reaction.
Reported exposure to any adversity in childhood was
significantly associated with being a psychosis case in this
sample (unadjusted OR=2.80, 95% CI 1.66-4.74, p

O15.4 SEARCHING FOR GENES WITH
ENVIRONMENTAL INTERACTION IN COMPLEX
DISORDERS
K. Merikangas*
*merikank@mail.nih.gov
O16 ALCOHOL & SUBSTANCE ABUSE
O16.1 ASSOCIATION OF SUBSTANCE USE
DISORDERS WITH CHILDHOOD TRAUMA BUT NOT
AFRICAN GENETIC HERITAGE IN AN AFRICAN
AMERICAN COHORT
F. Ducci* (1), A. Roy (2), P. Shen (3), Q. Yuan (3), N. Yuan
(4), C. Hodgkinson (3), L. Goldman (5), D. Goldman (3)
1. Institute of Psychiatry, Kings College, London, UK
2. The Social, Genetic, and Developmental Psychiatry Centre,
Division of Psychological Medicine, Institute of Psychiatry;
the Psychiatry Service, Department of Veterans Affairs, New
Jersey VA 3. Laboratory of Neurogenetics, National Institute
on Alcohol Abuse and Alcoholism, Bethesda, Md 4. Mel and
Enid Zuckerman College of Public Health, University of
Arizona, Tucson 5. Department of Environmental Health
Sciences, Johns Hopkins Bloomberg School of Public Health,
Baltimore
*francesca.ducci@kcl.ac.uk
Objective: Genetic variation influences differential
vulnerability to addiction within populations. However, it
remains unclear whether differences in frequencies of
vulnerability alleles contribute to disparities between
populations and to what extent ancestry correlates with
differential exposure to environmental risk factors, including
poverty and trauma. Method: The authors used 186
ancestry-informative markers to measure African ancestry in
407 addicts and 457 comparison subjects self-identified as
African Americans. The reference group was 1,051
individuals from the Human Genome Diversity Cell Line
Panel, which includes 51 diverse populations representing
most worldwide genetic diversity. Results: African Americans
varied in degrees of African, European, Middle Eastern, and
Central Asian genetic heritage. The overall level of African
ancestry was actually smaller among cocaine, opiate, and
alcohol addicts (proportion=0.76–0.78) than nonaddicted
African American comparison subjects (proportion=0.81).
African ancestry was associated with living in impoverished
neighborhoods, a factor previously associated with risk. There
was no association between African ancestry and exposure to
childhood abuse or neglect, a factor that strongly predicted all
types of addictions. Conclusions: These results suggest that
African genetic heritage does not increase the likelihood of
genetic risk for addictions. They highlight the complex
interrelation between genetic ancestry and social, economic,
and environmental conditions and the strong relation of those
factors to addiction. Studies of epidemiological samples
characterized for genetic ancestry and social, psychological,
demographic, economic, cultural, and historical factors are
needed to better disentangle the effects of genetic and
environmental factors underlying interpopulation differences
in vulnerability to addiction and other health disparities.

O16.2 ASSOCIATIONS OF DRD1-D5, SLC18A2,
SLC6A3, DDC, AND TH WITH ALCOHOL
DEPENDENCE (AD) AND RELATED DISORDERS IN
THE IRISH AFFECTED SIB PAIR STUDY OF
ALCOHOL DEPENDENCE (IASPSAD)
L. Hack* (1), G. Kalsi (1), F. Aliev (1), P. Kuo (2), C.
Prescott (3), D. Patterson (4), D. Walsh (5), D. Dick (1), B.
Riley (1), K. Kendler (1)
1. Virginia Institute for Psychiatric and Behavioral Genetics,
Department of Psychiatry, Virginia Commonwealth
University, Richmond, VA, USA 2. Institute of Clinical
Medicine, College of Medicine, National Cheng Kung
University, Tainan, Taiwan 3. Department of Psychology,
University of Southern California, Los Angeles, CA, USA
4. Shaftesbury Square Hospital, Belfast, Northern Ireland,
United Kingdom 5. Health Research Board, Dublin, Ireland
* hacklm@vcu.edu
The mesocorticolimbic dopaminergic system is central to the
reward pathway. As a result, variation in dopamine genes may
contribute to liability for AD and related disorders. We
examined 10 dopamine genes (DRD1-D5, SLC18A2,
SLC6A3, DDC, TH and COMT) for association with AD and
alcohol-related traits in PLINK 1.05. The sample included 575
independent cases selected from the IASPSAD sample and
530 ethnically matched and screened controls. After data
cleaning, 101 SNPs were available for analysis. Only SNPs
surviving 5000 gene-based permutations are reported here. We
reasoned that gene-based correction was a sufficiently
conservative correction method because all selected genes
have a priori evidence of association with AD and/or related
phenotypes. For the dichotomous trait AD, we observed the
strongest signal within DRD4 (rs12280580: P=0.003;
OR=1.33) and a nominal signal within the dopamine
transporter, SLC6A3 (rs27048: P=0.04; OR=0.83). Analysis
of the quantitative alcohol-related traits (age at onset, initial
sensitivity, tolerance, max24, and withdrawal) yielded
association with initial sensitivity and DRD3 (p=0.002),
withdrawal and DRD5 (p=0.002), and weaker associations
with other traits. Because additional evidence indicates that
polymorphisms in dopamine genes contribute to other
externalizing phenotypes, we conducted secondary association
analyses on 6 of these traits, including symptoms for alcohol
dependence, antisocial personality disorder, attention
deficit/hyperactivity disorder, conduct disorder, drug
dependence, and scores for novelty seeking. We found that 7
DA genes were associated with one or more externalizing
phenotypes. Our study provides evidence that variation in
dopamine genes contributes to AD as well as a range of
externalizing traits.
O16.3 SPECIFIC AND NON-SPECIFIC GENETIC RISK
FACTORS FOR ALCOHOL USE: ANALYSES OF
DEVELOPMENTAL TRENDS AND
GENE-ENVIRONMENT INTERACTIONS
K. Kendler* (1), C. Prescott (2), D. Dick (1)
1. Virginia Institute for Psychiatric and Behavioral Genetics 2.
University of Southern California
* Kendler@vcu.edu
Although we know that the risk for alcohol dependence (AD)
is influenced by genetic factors both specific to alcohol and
for more general externalizing traits, we know little about how
these two classes of genetic risk act during development.
Furthermore, while environmental exposures can moderate the
impact of genetic risk factors on alcohol consumption (AC),
such studies have typically explored one environmental
exposure during a single developmental period. Use life-event
history retrospective data from 1,796 male twins from the
Virginia Twin Register, we found that non-specific genetic
risk for externalizing disorders impacts maximally on AC at
ages 15-17 and then declines in importance. By contrast,
specific genetic risks for AD have maximal and more enduring
effects on AC starting at ages 18-21. We also find interactions
between these genetic risks and 5 key environmental variables
(parental monitoring, peer deviance, alcohol availability,
prosocial behaviors and parental bonding) early in
adolescence. As individuals age, the main effects of these
environments on AC become more prominent while their
interactions with genetic effects diminish. Genetic effects on
AC appear to be much more environmentally sensitive at early
developmental stages. Finally, in 5,072 male and female adult
drinking twins from the Virginia Registry, we examined the
relationship between genetic risk for a common factor made
up of four measures of alcohol consumption during the period
of lifetime heaviest drinking (frequency, quantity, maximum
single-day consumption and frequency of drinking to
intoxication) and AD. A structural twin model produced very
high genetic correlations between the common factor and AD
(+0.88 in females and +0.91 in males). These quantitative
indices of alcohol consumption accurately reflected the
genetic risk for AD.

O16.4 RESEQUENCING OF NICOTINIC RECEPTOR
GENES AND ANALYSIS OF RARE AND COMMON
VARIATIONS WITH NICOTINE DEPENDENCE
J. Wessel* (1), D. Hinds (2), M. Kennemer (2), S. Pitts (2), R.
Stokowski (2), D. Ballinger (2), J. McClure (3), L. Jack (1), J.
Hardin (1), G. Swan (1), A. Bergen (1)
1. SRI International 2. Perlegen Sciences 3. Group Health
*jennifer.wessel@sri.com
Genome-wide association studies have identified a few
common single nucleotide polymorphisms (SNPs) associated
with nicotine dependence but only a small portion of the
heritability can be explained. We set out to determine if rare
and common SNPs identified from sequencing of nicotinic
receptor genes in a large sample of individuals could further
explain the genetic basis of nicotine dependence. Exons of ten
nicotinic receptor genes (CHRNA2-7, CHRNB1-4) were
resequenced with 454 technology using DNA from saliva in
448 European-Americans of a smoking cessation trial. We
tested for associations of common and rare variations with the
Fagerström Test of Nicotine Dependence (FTND) using
standard linear and logistic regression methods for common
SNPs and recently developed methods for rare SNPs, the
cohort allelic sum test (CAST), the weighted sum statistic
(WSS), and the multivariate distance matrix regression
(MDMR) method. 166 SNPs were identified, 16.3% had
reduced completion rate and were excluded from analyses,
74.1% had minor allele frequencies .05), but the
MDMR showed significant associations with all CHRNB2
SNPs by allele sharing (p=0.004) or weighted allele frequency
(p=0.003). CHRNB2 common and rare variants exhibited
significant association to FTND in this sample.
O17 DEMENTIA AND MEMORY
O17.1 GENOME-WIDE ASSOCIATION STUDY OF
ALZHEIMER'S DISEASE
D. Harold* (1), R. Abraham (1), P. Hollingworth (1), R. Sims
(1), A. Gerrish (1), M. Hamshere (1), S. Lovestone (2), C.
Brayne (3), D. Rubinsztein (3), M. Gill (4), B. Lawlor (4), K.
Morgan (5), P. Passmore (6), M. Nöthen (7), W. Maier (7), G.
Livingston (8), N. Bass (8), A. Goate (9), S. Younkin (10), A.
Al-Chalabi (11), R. Gwilliam (12), P. Deloukas (12), P.
Holmans (1), M. O'Donovan (1), M. Owen (1), J. Williams (1)
1. Cardiff University 2. Institute of Psychiatry 3. University of
Cambridge 4. Trinity College Dublin 5. University of
Nottingham 6. Queen's University Belfast 7 University of
Bonn 8. University College London 9. Washington University
10. Mayo Clinic 11. Kings College London 12. Sanger
Institute
* wpcdhh@cf.ac.uk
Alzheimer’s disease (AD) is the most common form of
dementia and is highly heritable but genetically complex.
Neuropathologically, the disease is characterised by
extracellular senile plaques containing β-amyloid and
intracellular neurofibrillary tangles containing
hyperphosphorylated τ protein. Mutations of the amyloid
precursor protein (APP) gene and the presenilin 1 and 2 genes
(PSEN1, PSEN2) cause rare, Mendelian forms of the disease
usually with an early-onset. However, in the more common
form of AD, only apolipoprotein E (APOE) has been
established unequivocally as a susceptibility gene. Aiming to
identify novel AD loci, we undertook a two-stage
genome-wide association study of Alzheimer’s disease
involving over 16,000 individuals genotyped on Illumina
platforms. In stage 1 (3,941 cases and 7,848 controls), we
replicated the established association with the APOE locus
and observed genome-wide significant association with SNPs
at two novel independent loci (p

O17.2 IMPACT OF ALCOHOL ABUSE ON
ALZHEIMER DISEASE
M. Slifer (1), M. Cuccaro (1), J. Haines (2), M. Pericak-Vance
(1)
1. MIHG 2. Vanderbilt University
Background: Efforts to understand the Alzheimer Disease
(AD) phenotype have identified cardiovascular,
neuropsychiatric, and lifestyle factors that are associated with
the onset and course of AD. The relationship between alcohol
use and cognitive impairment is controversial. While generally
believed to be deleterious given its independent role in
promoting cognitive decline, several studies have found
moderate alcohol consumption to be protective.
Understanding the impact of history of excessive alcohol use
on individuals at risk for AD is critical given that alcohol use
is common in the aging population. Methods: This
retrospective study examined the relationship between remote
history of alcohol substance abuse (SA) and age of onset in
LOAD. These results were further analyzed as a function of
gender. Based on chart review of 294 cases, we identified 65
unrelated participants with LOAD and a remote history of SA.
History of SA was based on medical history data. All
participants were in sustained remission. All participants had
history, clinical presentation, and imaging (if available)
consistent with classic AD; all are classified as probable AD.
Age at onset (AAO) was defined on the basis of chart review
of age at functional impairment. Results: Individuals with a
history of SA and LOAD demonstrate a statistically
significant earlier age of onset (69.9y, SD=6.8y) vs. those
with LOAD and no history of SA (73.3y, SD=6.6y).
Sex-stratified analysis revealed that males with LOAD were
significantly more likely to have a history of SA vs. females
(odds ratio=4.5 (95% CI 2.4-8.3)). Depression was also more
prevalent among those with a history SA (69% vs. 40%).
There was no statistically significant difference in APOE
genotypes, or allele frquencies between those with SA and
LOAD versus those with LOAD alone. Conclusons: These
findings suggest that history of alcohol abuse may result in an
earlier age of onset for individuals at risk for developing
LOAD. There is no evidence that alcohol use results in AD
pathophysiology. However, alcohol abuse may exacerbate a
developing pattern of cognitive impairment in AD or
compromise/reduce cognitive reserves resulting in an earlier
onset. Given the tremendous health care costs associated with
AD, a widely cited objective is to delay onset of disease.
Factors which accelerate the course of the illness have the
potential to result in significant economic burden. Similarly,
quality of life for individuals and families is equally
compromised with an earlier onset.
O17.3 CNV GWAS FINDS RARE DELETIONS IN
THYROID HORMONE GENE ASSOCIATED WITH
ALZHEIMER’S DISEASE
C. Lambert* (1), G. Linse Peterson (1)
1. Golden Helix, Inc.
* lambert@goldenhelix.com
In numerous studies of Alzheimer’s disease (AD), thyroid
hormones and the genes that regulate them have been
associated with an increased risk of the disease. However,
few, if any, genome-wide Copy Number Variation (CNV)
studies have found associations with either rare or common
variants for AD. The presence of rare CNVs has been
suggested in the increased risk of schizophrenia and other
psychiatric disorders, and we hypothesize CNVs could be
associated with increased risk of AD as well. To this end, we
performed a genome-wide association test to identify CNVs
using log ratio data from an Affymetrix 500k array. The
cohort consisted of approximately 1600 Caucasians, with
roughly equal numbers of cases and controls (the average age
of onset was 72 years). While no common CNVs appeared to
be associated with AD, there were three femalecases with
large overlapping deletions (116 kilobases to 230 kilobases),
where the consensus region was 65 kilobases and spanned
approximately one-third of a thyroid hormone gene, with the
two larger deletions spanning the entire gene. The deletion
did not exist in any controls or in any males. Studies have
reported a link between thyroid hormones and AD,
particularly in women, further supporting this finding.
Replication studies are underway to confirm the variant’s
association with AD; results will be reported at this meeting.

O17.4 COMMON VARIANTS ASSOCIATED WITH
BRAIN ATROPHY IN ALZHEIMER’S DISEASE
PATIENTS
S. Furney (1), A. Simmons (1), K. Lunnon (1), G. Breen (1),
A. Hodges (1), S. Lovestone (1)
1. NIHR Biomedical Research Centre for Mental Health,
Institute of Psychiatry, King’s College London.
Alzheimer’s disease is the most common form of dementia
and affects more than 400,000 people in the U.K. In this study
we have tested the hypothesis that common genetic variation
has an affect on brain atrophy in Alzheimer’s disease patients
from the AddNeuroMed project. Over 300 European
individuals were categorised as Control, Mild Cognitive
Impairment (MCI) or Alzheimer’s disease (AD) by psychiatric
assessment. The individuals had T1 structural MRI scanning
from which entorhinal cortical thicknesses and whole brain
volumes were calculated. In addition, blood was taken from
the individuals and extracted DNA was run on the Illumina
Human 610-Quad Beadchip. We used 494419 SNPs from
across the genome (484465 autosomal) that had passed
stringent quality control thresholds of minor allele frequency
>0.05, a sample calling rate of 0.985, and a SNP calling rate of
0.99. Relatedness of the individuals was assessed by identity
by descent estimates. Population stratification was conducted
to identify any potential outlying individuals. HapMap Phase 2
SNPs from CEU founders were imputed in the samples.
A total of 239 individuals categorised as Control, Mild
Cognitive Impairment or Alzheimer’s disease passed the
genotyping quality control, were genotyped for ApoE and had
scanning data that passed quality control protocols. Entorhinal
cortical thicknesses and whole brain volumes were corrected
for age, sex, disease status and ApoE4 dosage. An additive
model was applied to investigate the interaction between
individual allele dosage and MCI or AD status. A number of
SNPS were assigned p-values

POSTER
ABSTRACTS

ADHD
1 THE ROLE OF THE Y CHROMOSOME IN
NEURODEVELOPMENTAL DISORDERS
E. Stergiakouli* (1), H. Williams (1), K. Langley (1), A.
Thapar (1), M. Owen (1)
1. Department of Psychological Medicine, Cardiff University,
Henry Wellcome Building, Heath Park CF14 4XN, Cardiff,
U.K.
*stergiakouliE@cardiff.ac.uk
ADHD and schizophrenia are neurodevelopmental disorders
that are more prevalent in males. Both disorders also show sex
differences in age of onset or severity. The Y chromosome is
potentially an important influence on male susceptibility to
neuropsychiatric disorders. The way the Y chromosome can
increase risk to neuropsychiatric disorders is directly or
indirectly by interacting with autosomal genes expressed in
the brain or with environmental factors. In addition, it can
modify the disease phenotype by influencing cognitive
performance. However, due to difficulties arising from the
lack of recombination and widely accepted nomenclature, the
Y chromosome has been largely excluded from genetic and
genomic studies of neuropsychiatric disorders. In order to
overcome this lack of knowledge, we chose to study the Y
chromosome in a sample of 210 cases with ADHD, 310 cases
with schizophrenia and 700 U.K. controls. In total, 11 Y
chromosome markers were selected to represent the main Y
chromosome haplogroups that are present in the U.K.
according to data from the Y chromosome Consortium and
personal communication with Y chromosome researchers.
Statistical analysis of Y chromosome haplogroups revealed
that although there was no significantly increased
representation of any haplogroup in cases with ADHD or
schizophrenia compared to controls, specific Y chromosome
haplogroups were associated with higher performance and full
scale IQ within the ADHD sample. Our results provide
evidence that Y chromosome variation may modify ADHD
phenotype by influencing cognitive performance.
2 INFLUENCE OF DAT1 POLYMORPHISM ON
STRIATAL ACTIVATION IN ADULT ADHD
M. Hoogman* (1), E. Aarts (2), M. Zwiers (2), D.
Slaats-Willemse (3), R. Cools (2), C. Kan (1), J. Buitelaar (1),
B. Franke (4)
1. Department of Psychiatry, Donders Institute for Brain,
Cognition and Behaviour, Radboud University Nijmegen
(Medical Centre), Nijmegen 2. Donders Centre for Cognitive
Neuroimaging, Donders Institute for Brain, Cognition and
Behaviour, Radboud University Nijmegen (Medical Centre),
Nijmegen 3. Karakter Child and Adolescent Psychiatric
Centre, Nijmegen, The Netherlands 4. Department of Human
Genetics, Donders Institute for Brain, Cognition and
Behaviour, Radboud University Nijmegen (Medical Centre),
Nijmegen
*m.hoogman@psy.umcn.nl
Background: Attention Deficit/Hyperactivity Disorder
(ADHD) is characterised by altered reward processing and
striatal hypoactivity during reward tasks. The striatal reward
processing centre has a high dopamine transporter (DAT)
density. A VNTR in the 3’ UTR of DAT1, a risk factor for
ADHD, alters gene expression and influences dopamine
transporter density in the striatum and levels of synaptic
dopamine. Our objective is to explore the influence of this
polymorphism on functionality of the striatum in adult ADHD.
Methods: So far, twenty-eight adults meeting criteria for
DSM-IV ADHD and nineteen healthy subjects have been
recruited. Recruitment is still ongoing. Participants perform a
reward anticipation task inside a 1.5 Tesla MR scanner
(adapted from Knutson et al., 2001). Statistical analysis
compares the ventral striatal BOLD response of groups based
on genotype (10/10-repeat homozygotes versus 9-repeat
carriers). Results: Interim analysis already reveals more
ventral striatal activity in 10/10-repeat homozygotes in ADHD
patients (p=0.03). The exact opposite effect is found in healthy
individuals (p=0.02; interaction genotype x disorder:
p=0.002). Genotype or disorder does not affect behavioral
measures. Discussion: These results could be explained by the
added effect of an excess of striatal phasic dopamine (DA) in
ADHD patients and less DAT availability in 9-repeat carriers
to transport DA. Therefore an overdose of DA might lead to
less striatal activation. This study can help to explain why the
9-repeat allele of the DAT1 VNTR is a risk factor for adult
ADHD (Franke et al, 2008).

3 META-ANALYSIS OF THE SLC6A3/DAT1 VNTR
HAPLOTYPE IN PERSISTENT ADHD SUGGESTS
DIFFERENTIAL INVOLVEMENT OF THE GENE IN
CHILDHOOD AND PERSISTENT ADHD
B. Franke* (1, 2), S. Johansson (3, 4), K. Lesch (5), P.
Asherson (6), S. Faraone (7), E. Mick (8), J. Buitelaar (2), J.
Haavik (3, 9), B. Cormand (11), J. Ramos-Quiroga (10), A.
Reif (5)
1. Department of Human Genetics, Donders Institute for
Brain, Cognition and Behavior, Centre for Neuroscience,
Radboud University Nijmegen Medical Centre, Nijmegen,
The Netherlands 2. Department of Psychiatry, Donders
Institute for Brain, Cognition and Behavior, Centre for
Neuroscience, Radboud University Nijmegen Medical Centre,
Nijmegen, The Netherlands 3. Department of Biomedicine,
University of Bergen 4. Center for Medical Genetics and
Molecular Medicine, Haukeland University Hospital, Bergen,
Norway 5. Department of Psychiatry and Psychotherapy,
Clinical and Molecular Psychobiology, and Interdisciplinary
Center for Clinical Research (IZKF), University of Würzburg,
Würzburg, Germany 6. MRC Social Genetic and
Developmental Psychiatry, Institute of Psychiatry, Kings
College London, London, UK 7. Departments of Psychiatry
and Neuroscience and Physiology, SUNY Upstate Medical
University, Syracuse, New York, USA 8. Department of
Psychiatry, Massachusetts General Hospital and Harvard
Medical School, Boston, MA, USA 9. Department of
Psychiatry, Haukeland University Hospital, Bergen, Norway
10. Department de Genètica, Facultat de Biologia, Universitat
de Barcelona, CIBER Enfermedades Raras, Instituto de Salud
Carlos III, Barcelona, and Institut de Biomedicina de la
Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain
11. Department of Psychiatry, Hospital Universitari Vall
d’Hebron, Barcelona, and Department of Psychiatry and Legal
Medicine, Universitat Autònoma de Barcelona, Catalonia,
Spain
*b.franke@antrg.umcn.nl
Attention-deficit/hyperactivity disorder (ADHD) is one of the
most common neuropsychiatric disorders with a worldwide
prevalence around 4-5% in children and 1-4% in adults.
Although ADHD is highly heritable and familial risk may
contribute most strongly to the persistent form of the disorder,
there are few studies of the genetics of ADHD in adults. In the
current paper, we present results of the International
Multicentre Persistent ADHD Genetics CollaboraTion
(IMpACT) that has been set up with the goal of performing
research into the genetics of persistent ADHD. A
meta-analysis of the SLC6A3/DAT1 gene in persistent ADHD
was carried out in 1440 patients and 1769 controls from
IMpACT and one earlier report. DAT1, encoding the
dopamine transporter, is one of the most frequently studied
genes in ADHD, though results have been inconsistent. A
variable number tandem repeat polymorphism (VNTR) in the
3’ untranslated region (UTR) of the gene and, more recently, a
haplotype of this VNTR with another VNTR in intron 8 have
been the target of most studies. Whereas the 10/10 genotype of
the 3’ UTR VNTR and the 10-6 haplotype of the two VNTRs
are thought to be risk factors for ADHD in children, we found
the 9/9 genotype (p=0.03) and the 9-6 haplotype (p=0.03)
associated with persistent ADHD. A differential association of
DAT1 with ADHD in children and in adults might help
explain the inconsistencies observed in earlier association
studies. However, the data might also imply that DAT1 plays
a modulatory rather than causative role in ADHD.
4 FURTHER INVESTIGATION OF THE STEROID
SULFATASE (STS) GENE AND ADHD: ASSOCIATION
AND MOLECULAR ANALYSES
K. Brookes* (1), Z. Hawi (2), J. Park (1), S. Scott (1), A.
Kirley (2), E. Barry (2), D. Coghill (3), M. Gill (2), L. Kent
(1)
1. Bute Medical School, University of St Andrews, St
Andrews, UK 2. Department of Psychiatry, Trinity Centre for
Health Sciences, St James’s Hospital, Dublin, Ireland 3.
Division of Medical Sciences, Centre for Neuroscience,
University of Dundee, Scotland
*kjb11@st-andrews.ac.uk
Attention Deficit Hyperactivity Disorder (ADHD) is one of
the most heritable and prevalent behavioural disorders
affecting 3-5% of school-aged children. Evidence from animal
and human studies suggests steroid sulphatase (STS) may
influence aspects of attention. Using tagging SNP’s we
previously demonstrated that genetic variation in the STS gene
is associated with ADHD. This study extends those initial
findings by fine mapping the 5’ region of the STS gene using
twelve SNP markers in an extended sample of 450 probands,
of which the majority were male (90.1%) between the ages of
4 – 15 years. The majority of the sample was diagnosed as
ADHD combined subtype (82.3%), with comorbidity rates of
46.9% for Oppositional Defiant Disorder, and 15.3% for
Conduct Disorder. Additionally, STS protein and RNA were
isolated from twenty-eight normal post-mortem brains in order
to investigate the functionality of associated polymorphisms,
by western blotting and mRNA gene expression. Results
indicated that six SNP’s were associated with ADHD (with a
significance value of P less than 0.05 for each individual
marker) spanning the first two introns of the STS gene and one
within a known alternative first exon. Haplotype analysis
using the Gabriel method indicated two haplotype blocks, both
of which were significantly associated with ADHD (P=0.001
and P=0.004). mRNA expression and protein levels were not
related to any of the significantly associated SNP markers.

5 CADHERIN 13 IS IMPLICATED IN ADULT ADHD,
ITS ENDOPHENOTYPES AND CO-MORBID
CONDITIONS
A. Reif* (1), T. Nguyen (2), L. Weissflog (1), C. Jacob (1), M.
Romanos (1), S. Liedel (1), H. Schäfer (2), A. Warnke (1), B.
Cormand (3), J. Haavik (4), B. Franke (5), K. Lesch (1)
1. University of Würzburg 2. University of Marburg 3.
University of Barcelona 4. University of Bergen 5. University
of Nijmegen
*reif_a@klinik.uni-wuerzburg.de
The atypical cadherin 13 (CDH13) has hitherto mainly gained
attention regarding its function in the heart, where it has an
important role in cell-cell adhesion. However, it is also
expressed in the brain with a remarkable expression pattern,
and with transcripts found in the prefrontal cortex, thalamus,
the raphe nuclei and the locus coeruleus, CDH13 is in the
center of monoaminergic neurotransmission. In the last year,
several genome-wide association studies (GWAS) provided
evidence that CDH13 is associated with different substance
abuse disorders and quite interestingly, CDH13 was also
amongst the top hits of two GWAS in ADHD (Lesch et al.,
2008; Lasky-Su et al., 2008). Further evidence for a role of
CDH13 in ADHD was provided by a meta-analysis of ADHD
linkage studies, where the locus containing CDH13 was the
only one to reach genome-wide significance (Zhou et al.,
2008). Thus, CDH13 is a highly relevant candidate gene for
ADHD and related conditions. We have tested an association
of CDH13 with adult ADHD (aADHD) interrogating 86
tagging SNPs in a sample of 624 aADHD cases and 422
controls. Thereby, several SNPs scattered across the gene
were found to be associated with disease, co-morbid
conditions such as depression, as well as NEO Extraversion
and TPQ Novelty Seeking. 14 SNPs had p-values < 0.01, and
within two haploblocks a significant association of a
haplotype with aADHD was observed. To replicate this
finding, we additionally tested a family-based sample
consisting of 170 families with at least one child affected with
ADHD. Again, seven SNPs in this sample were associated
with disease. Joint analysis revealed that five SNPs and two
haplotypes, each including one of the risk alleles, were
associated with disease in both samples. Further replication
was aimed for in the IMpACT sample consisting of more than
1,000 additional aADHD cases from three European countries.
Taken all findings together, CDH13 appears to be a highly
relevant gene for disorders with the shared feature of deficient
impulse control such as ADHD and substance abuse. The
corresponding pathomechanism might include defective
monoaminergic neurotransmission. This latter hypothesis has
yet to be established, and respective analyses are underway.
6 RIGHT-SIDED SPATIAL DIFFICULTIES IN ADHD
DEMONSTRATED IN CONTINUOUS MOVEMENT
CONTROL
K. Johnson* (1), A. Dáibhis (2), C. Tobin (2), R. Acheson
(2), A. Watchorn (2), A. Mulligan (3), E. Barry (2), J.
Bradshaw (4), M. Gill (2), I. Robertson (2)
1. Queen's University of Belfast 2. Trinity College Dublin 3.
Mater Hospital 4. Monash University
* k.johnson@qub.ac.uk
Attention Deficit Hyperactivity Disorder (ADHD) is a
prevalent neurodevelopmental psychiatric disorder
characterised by hyperactivity, inattention and impulsiveness.
Children with ADHD often show spatial attentional deficits,
exhibiting a subtle rightwards bias, possibly due to
dysfunction within the right hemisphere fronto-parietal
network. Approximately 50% of children with ADHD also
show signs of movement dysfunction. This movement
dysfunction, however, has not been clearly described. Some
areas of the brain involved in movement control (the
fronto-striatal circuits) show anatomical and physiological
dysfunction in ADHD. This study compared 31 children with
and 31 children without ADHD on a movement kinematic task
that tested hand-drawing movement precision, using the same
procedure as Mattingley et al., (1994) and Phillips et al.,
(1996). Participants used an electronic pen on a WACOM
Intuos3 PTZ930 A4-sized digitizing tablet. The pen tip
position was sampled as X and Y coordinates at 200 Hz, with
an accuracy of ±0.25 mm. Data were acquired using the
MovAlyzer® software package, on a laptop computer. The
task was to join targets of either 10 or 20mm diameter that
were separated by a distance of 62.5 or 125mm. Constant
error in the X and Y planes, peak vertical velocity and
acceleration, and movement time were analysed. Apart from a
significantly increased rate of acceleration across all
conditions, the children with ADHD demonstrated no
temporal difficulties with the task; rather they showed subtle
spatial difficulties. The children with ADHD showed
difficulties in accuracy of movement towards the right. They
were less accurate in the X plane when moving towards the
right-sided targets over the long distance. Greater variability
in target accuracy was shown when moving towards the small
target on the right side. These results suggest that the subtle
spatial bias towards the right that has been demonstrated in
ADHD on visual spatial tasks also extends into the movement
domain.

7 COMMON VARIANTS IN THE TPH1 AND TPH2
REGIONS ARE NOT ASSOCIATED WITH
PERSISTENT ADHD IN 3559 INDIVIDUALS FROM
FOUR EUROPEAN POPULATIONS
S. Johansson* (1, 2), A. Halmøy (1), T. Mavroconstanti (1),
K. Jacobsen (1), E. Landaas (1), A. Reif (3), C. Jacob (3), A.
Boreatti-Hummer (3), S. Kreiker (3), K. Lesch (3), C. Kan (4),
J. Kooij (5), L. Kiemeney (6), J. Buitelaar (4), B. Franke (4),
M. Ribases (7), R. Bosch (7), M. Bayes (8), M. Casas (7), J.
Ramos-Quiroga (7), B. Cormand (9), P. Knappskog (2), J.
Haavik (1, 10)
1. Department of Biomedicine, University of Bergen, Norway
2. Center for Medical Genetics and Molecular Medicine,
Haukeland University Hospital. Bergen, Norway 3.
Department of Psychiatry, Psychosomatics and
Psychotherapy, University of Würzburg, Würzburg, Germany
4. Department of Psychiatry, Donders Institute for Brain,
Cognition and Behavior, Radboud University Nijmegen
Medical Centre, Nijmegen, The Netherlands 5. Parnassia,
Psycho-Medical Centre, The Hague, The Netherlands 6.
Department of Epidemiology & Biostatistics, Radboud
University Nijmegen Medical Centre, Nijmegen, The
Netherlands 7. Department of Psychiatry, Hospital
Universitari Vall d’Hebron, Barcelona, Catalonia, Spain 8.
Genes and Disease Program, Center for Genomic Regulation
(CRG-UPF), Barcelona, Catalonia, Spain 9. Departament de
Genètica, Facultat de Biologia, Universitat de Barcelona,
Catalonia, Spain 10. Division of Psychiatry, Haukeland
University Hospital, Bergen, Norway.
* stefan.johansson@biomed.uib.no
The tryptophan hydroxylase 1 and 2 (TPH1 and TPH2) genes
which encode the rate-limiting enzymes in the serotonin
biosynthesis have been implicated in several psychiatric
disorders. Results from children with
attention-deficit/hyperactivity disorder (ADHD) are
conflicting, and little is known about TPH1 and TPH2 in adult
ADHD patients. We therefore first genotype-tagged all
common variants within both genes in a Norwegian sample of
451 patients with a diagnosis of adult ADHD and 584
controls. Six of the SNPs were subsequently genotyped in
three additional independent European Caucasian samples of
adult ADHD cases and controls from the International
Multicenter persistent ADHD CollaboraTion (IMpACT).
None of the SNPs reached formal study-wide significance in
the total meta-analysis sample of 1636 cases and 1923
controls, despite having a power of >80% to detect a variant
conferring an OR=1.25 at P=0.001-level. However,
rs17794760 located in TPH1 showed nominal significance
[OR=0.84 (0.71-1.00), P=0.05]. In conclusion, in the single
largest ADHD genetic study of TPH1 and TPH2 variants
presented to date (n=3559 individuals) we did not find
consistent evidence for a major effect of common genetic
variants on persistent ADHD.
8 CASE-CONTROL STUDY OF SIX GENES
ASYMMETRICALLY EXPRESSED IN THE TWO
CEREBRAL HEMISPHERES: ASSOCIATION OF
BAIAP2 WITH ADHD
M. Ribasés* (1), R. Bosch (1), A. Hervás (2), J.
Ramos-Quiroga (1), C. Sánchez-Mora (1), A. Bielsa (1), X.
Gastaminza (1), S. Guijarro-Domingo (2), M. Nogueira (1), N.
Gómez-Barros (1), S. Kreiker (3), S. Groß-Lesch (3), C. Jacob
(3), K. Lesch (3), A. Reif (3), S. Johansson (4), K. von Plessen
(5), P. Knappskog (6), J. Haavik (4), X. Estivill (7), M. Casas
(1), M. Bayés (7), B. Cormand (8)
1. Department of Psychiatry, Hospital Universitari Vall
d’Hebron, Barcelona, Catalonia, Spain 2. Child and
Adolescent Mental Health Unit, Hospital Mútua de Terrassa,
Barcelona, Spain 3. Department of Psychiatry,
Psychosomatics and Psychotherapy, University of Würzburg,
Füchsleinstr. Würzburg, Germany 4. Department of
Biomedicine, University of Bergen, Norway 5. Division of
Psychiatry, Haukeland University Hospital, Bergen, Norway
6. Center of Medical Genetics and Molecular Medicine,
Haukeland University Hospital, Norway 7. Genes and Disease
Program, Center for Genomic Regulation (CRG-UPF,)
Barcelona, Spain 8. Departament de Genètica, Facultat de
Biologia, Universitat de Barcelona, Spain
* marta.ribases@gmail.com
Attention-deficit hyperactivity disorder (ADHD) is a
childhood-onset neuropsychiatric disease that persists into
adulthood in at least 30% of ADHD children. Different lines
of evidence suggest that abnormal left-right brain asymmetries
in ADHD patients may be involved in a variety of
ADHD-related cognitive processes. Although mechanisms
underlying cerebral lateralization are unknown, left-right
cortical asymmetry in humans has been associated with
transcriptional asymmetry at embryonic stages and a number
of genes differentially expressed between hemispheres have
been identified. We selected six functional candidate genes
showing at least 1.9-fold differential expression between
hemispheres (BAIAP2, DAPPER1, LMO4, NEUROD6,
ATP2B3 and ID2) and performed a case-control analysis in an
initial Spanish sample of 587 ADHD patients (270 adults and
317 children) and 587 controls. The single- and
multiple-marker analysis provided evidence for a contribution
of BAIAP2 to adulthood ADHD (P=0.0026, OR=1.69
(1.20-2.44) and P=0.0016, OR=1.64 (1.20-2.22), respectively).
We then tested BAIAP2 for replication in two independent
adult samples from Germany (639 ADHD patients and 612
controls) and Norway (417 ADHD cases and 469 controls)
contributed by the International Multicentre Persistent ADHD
CollaboraTion (IMpACT). While no significant results were
observed in the Norwegian sample, we replicated the initial
association between BAIAP2 and adulthood ADHD in the
German population (P=0.0062; OR=1.21 (1.03-1.42)). Our
results support the participation of BAIAP2 in the continuity
of ADHD across lifespan, at least in some of the populations
analyzed, and suggest that genetic factors potentially
influencing abnormal cerebral lateralization may be involved
in this neurodevelopmental disorder.

9 META-ANALYSIS OF BRAIN-DERIVED
NEUROTROPHIC FACTOR P.VAL66MET IN ADULT
ADHD IN FOUR EUROPEAN POPULATIONS
C. Sánchez-Mora* (1), M. Ribasés (1), J. Ramos-Quiroga
(1), M. Casas (2), R. Bosch (2), A. Boreatti-Hümmer (3), M.
Heine (3), C. Jacob (3), K. Lesch (3), O. Fasmer (4), P.
Knappskog (5), J. Kooij (6), C. Kan (7), J. Buitelaar (7), E.
Mick (8), P. Asherson (9), S. Faraone (10), B. Franke (7), S.
Johansson (5), J. Haavik (4), A. Reif (4), M. Bayés (11), B.
Cormand (12)
1. Department of Psychiatry, Hospital Universitari Vall
d’Hebron, Barcelona, Catalonia, Spain 2. Hospital Universitari
Vall d’Hebron, Barcelona, Catalonia, Spain 3. Department of
Psychiatry, Psychosomatics and Psychotherapy, University of
Würzburg, Füchsleinstr. 15, 97080 Würzburg, Germany 4.
Division of Psychiatry, Haukeland University Hospital,
Bergen, Norway 5. Center of Medical Genetics and Molecular
Medicine, Haukeland University Hospital, Norway 6. PsyQ,
Psycho-Medical Programs, Program Adult ADHD, The
Hague, The Netherlands 7. Department of Psychiatry,
Radboud University Nijmegen Medical Centre, Nijmegen,
The Netherlands 8. Department of Psychiatry, Massachusetts
General Hospital and Harvard Medical School, Boston, MA,
USA 9. Social, Genetic, and Developmental Psychiatry
Centre, Institute of Psychiatry, King’s College London,
London, UK 10. Department of Neuroscience, SUNY Upstate
Medical University, Syracuse, New York 11. Genes and
Disease Program, Center for Genomic Regulation
(CRG-UPF,) Barcelona, Catalonia, Spain 12. Departament de
Genètica, Facultat de Biologia, Universitat de Barcelona,
Catalonia, Spain
* crissanchez@ir.vhebron.net
Attention-deficit hyperactivity disorder (ADHD) is a
multifactorial, neurodevelopmental disorder that often persists
into adolescence and adulthood and is characterized by
inattention, hyperactivity and impulsiveness. Before the
advent of the first genome-wide association studies in ADHD,
genetic research had mainly focused on candidate genes
related to the dopaminergic and serotoninergic systems,
although several other genes had also been assessed.
Pharmacological data, analysis of animal models and
association studies suggest that Brain-Derived Neurotrophic
Factor (BDNF) is also a strong candidate gene for ADHD.
Several polymorphisms in BDNF have been reported and
studied in psychiatric disorders but the most frequent is the
p.Val66Met (rs6265G>A) single nucleotide polymorphism
(SNP), with functional effects on the intracellular trafficking
and secretion of the protein. To deal with the inconsistency
raised among different case–control and family-based
association studies regarding the p.Val66Met contribution to
ADHD, we performed a meta-analysis of published as well as
unpublished data from four different centres that are part of
the International Multicentre Persistent ADHD CollaboraTion
(IMpACT). A total of 1,445 adulthood ADHD patients and
2,247 sex-matched controls were available for the study. No
association between the p.Val66Met polymorphism and
ADHD was found in any of the four populations or in the
pooled sample. The meta-analysis also showed that the overall
gene effect for ADHD was not statistically significant when
gender or comorbidity with mood disorders were considered.
Despite the potential role of BDNF in ADHD, our data do not
support the involvement of p.Val66Met in the pathogenesis of
this neuropsychiatric disorder.
10 EVIDENCE THAT GENETIC VARIATION IN THE
OXYTOCIN RECEPTOR GENE INFLUENCES SOCIAL
COGNITION SCORES IN ADHD
J. Park* (1), G. Vetuz (1), C. Toye (1), E. Barry (2), A.
Kirley (2), Z. Hawi (2), K. Brookes (2), M. Gill (2), L. Kent
(1)
1. Bute Medical School, University of St Andrews, St
Andrews, Scotland 2. Department of Psychiatry, Trinity
Centre for Health Sciences, St James’s Hospital, Dublin,
Ireland
* jp81@st-andrews.ac.uk
Attention Deficit Hyperactivity Disorder (ADHD) is a highly
heritable, common disorder of childhood. Recent evidence
demonstrates that ADHD and autistic traits share some genetic
liability, and both children with ADHD and autism have social
cognition deficits. Evidence from animal and human studies
implicates the oxytocin system in the development of social
cognition and previous association studies have reported
significant findings for genetic variation in the oxytocin
receptor (OXTR) gene with autism. This study therefore
investigated whether polymorphisms in the OXTR gene were
associated with either the ADHD phenotype or social
cognition traits in ADHD probands.This study employed a
family association sample consisting of 450 probands, aged 4
– 15 years, of which 90.1% were male. The majority of the
sample was diagnosed as ADHD combined subtype (82.3%),
with 46.9% comorbid for Oppositional Defiant Disorder, and
15.3% for Conduct Disorder. Additionally, 119 of the
probands completed the Social and Communication Disorders
Checklist (SCDC), with higher scores indicating poorer social
cognition. No statistical significant difference in SCDC score
between males and females was found. 5 single nucleotide
polymorphisms (SNP’s) in the OXTR gene previously
investigated in autism susceptibility were genotyped. No
significant associations with the ADHD phenotype were found
but a significant association between rs53576 genotype groups
and SCDC scores was discovered (F= 4.566, p= 0.013).
Post-hoc tests demonstrated the G allele of rs53576 to be
associated with poorer social cognition. This SNP lies in an
intronic 3 haplotype previously associated with autism.
Further investigation of these findings is warranted.

11 GENOMEWIDE ASSOCIATION SCAN OF
REACTION TIME DATA IN COMBINED TYPE ADHD
A. Vasquez (1), P. Asherson* (2), A. Wood (2), N. Rommelse
(1), F. Rijsdijk (2), B. Franke (1), K. Zhou (2), T.
Banaschewski (3), A. Rothenberger (4), R. Oades (5), M. Gill
(6), R. Ebstein (7), H. Roeyers (8), I. Manor (9), A. Miranda
(10), F. Mulas (10), H. Steinhausen (11), E. Sonuga-Barke
(12), J. Buitelaar (1), J. Sergeant (13), S. Faraone (14), J.
Kuntsi (2)
1. Department of Psychiatry, Radboud University, Nimjmegan
Medical Centre, Nijmegan, Netherlands 2. MRC Social
Genetic and Developmental Psychiatry, Institute of
Psychiatry, Kings College London, London, UK 3.
Department of child and adolescent psychiatry and
psychotherapy, University of Mannheim, Mannheim,
Germany 4. Child and adolescent psychiatry, University of
Goettingen, Goettingen, Germany 5. University Clinic for
child and adolescent psychiatry, Essen, Germany 6.
Department of Psychiatry, Trinity Centre for Health Sciences,
Dublin, Ireland 7. Herzog Memorial Hospital, Jerusalem,
Israel 8. Department of Experimental Clinical Health
Psychology, Ghent University, Ghent, Belgium 9. ADHD
clinic, Geha Mental Health Center, Petak-Tikvah, Israel 10.
Department of developmental and educational psychology,
University of Valencia, Valencia, Spain 11. Department of
child and adolescent psychiatry, University of Zurich, Zurich,
Switzerland 12. Institute for disorders of impulsivity and
attention, University of Southampton 13. Vrije Universiteit, de
Boelelaan, Amsterdam, Netherlands 14. Departments of
Psychiatry, Neuroscience and Physiology, SUNY Upstate
Medical University, Syracuse, United States
* p.asherson@iop.kcl.ac.uk
Results from multivariate familial model fitting on a large
sample of ADHD and control sibling-pairs indicate the
presence of two familial cognitive impairment factors (Kuntsi
et al., in preparation). The larger factor, reflecting 70% of the
familial variance with ADHD, captured all familial influences
on mean reaction time (RT) and RT variability. The second
factor, reflecting 20% of the familial variance with ADHD,
captured all familial influences on omission errors on the
go/no-go task and 60% of those on commission errors. These
findings suggest partially separable genetic influences that
contribute to the heritability of ADHD; RT variables represent
important indices of underlying genetic liability. We therefore
adopted a genome-wide scan approach to search for genes
associated with RT measures. The sample consisted of two
datasets from the International ADHD Multicentre Genetics
(IMAGE) project: the 8-team collaborative dataset derived RT
data from go/no-go and 4-choice reaction time tasks; the
Dutch dataset derived RT data from the Stop task. To evaluate
whether the two datasets could be combined we used Full
Information Maximum Likelihood Estimation to estimate
phenotypic (0.73–0.75) and familial (0.91–0.81) correlations
for mean RT and RT variability, respectively, between the
two-datasets. The final sample consists of around 500 ADHD
combined type probands plus their siblings for whom we had
both genomewide scan and RT data. Missing sibling GWAS
data is imputed using known IBD information from linkage
scan data. Further studies will aim to replicate these findings
through international collaborations of RT data in ADHD.
12 INVESTIGATION OF CANDIDATE GENE
INTERACTIONS INFLUENCING RISK FOR ADHD
R. Segurado* (1), M. Bellgrove, M. Gill (2), Z. Hawi (2)
1. Trinity College Dublin 2. T.C.D.
* rsegurdo@tcd.ie
A number of genes with function related to synaptic
neurochemistry have been associated with an
Attention-Deficit/Hyperactivity Disorder. However,
susceptibility to the development of common psychiatric
disorders by single variants acting alone, have so far only
explained a small proportion of the heritability of the
phenotype. It has been postulated that the unexplained “dark
heritability” may at least in part be due to epistatic effects,
which would explain the small observed main effects and the
difficulties in replication of positive findings. We undertook a
comprehensive exploration of pair-wise interactions between
150 genetic variants in 25 candidate genes involved in
monoaminergic catabolism, anabolism, release, re-uptake and
signal transmission, in a sample of 177 parent-affected child
trios using a case-only design. Marker-pairs showing large
effects and statistical significance were further explored with a
case-pseudocontrol design using conditional logistic
regression. We detected a number of moderate interaction
odds ratios (1.7 – 2.8), including between markers in the
ADRA1A and HTR2A genes, and markers in the HTR1B and
SLC18A2 genes. These effects are no larger than you would
expect by chance under the assumption of independence of all
pair-wise relations, however independence is unlikely.
Furthermore, the size of these effects is of interest and
attempts to replicate these results in other samples are
anticipated.

13 PHARMACOGENETICS ANALYSIS BETWEEN
THE DOPAMINE TRANSPORTER GENE AND
METHYLPHENIDATE RESPONSE IN CHILDREN
WITH ATTENTION-DEFICIT/HYPERACTIVITY
DISORDER
J. Genro* (1), C. Zeni (1), G. Polanczyk (1), T. Roman (1), R.
Luis (1), M. Hutz (1)
1. UFRGS
* juliagenro@hotmail.com
The gene DAT1 (SLC6A3) is the main candidate in
pharmacogenetics studies with ADHD because this transporter
is the major site of methylphenidate (MPH) action. All
association studies between DAT1 and MPH response have
focused in the 3’ VNTR of the gene presenting conflicting
results. The objective in this study is to verify if the variant
-839 C/T (rs2652512) located in the promoter region of the
gene is associated with response to MPH. A sample of 200
children from an ADHD outpatient clinic was genotyped for
the promoter polymorphism. The outcome measure was the
parent-rated oppositional subscale of the Swanson, Nolan and
Pelham Scale - version IV. The scale was applied by child
psychiatrists blinded to genotype at baseline and in the first
and third months of treatment. Data were analyzed using an
ANOVA model for repeated measures. Patients homozygous
for the T allele had a greater reduction in symptoms of
opposition (p = 0.003) and inattention (p = 0.004) compared
with patients with C allele over the 3 months of treatment.
These results suggest that response to MPH in children with
ADHD is influenced by genotype of the polymorphism -839
C/T of the DAT1 gene. The DAT1 promoter region may
influence response to treatment with MPH as well as
susceptibility to ADHD.
14 LACK OF ASSOCIATION BETWEEN THREE DAT1
POLYMORPHISMS AND RESPONSE TO
METHYLPHENIDATE IN ADULTS WITH ADHD
V. Contini* (1), M. Victor (2), G. Bertuzzi (1), E. Grevet (3),
C. Salgado (3), P. Belmonte-de-Abreu (2)
1. Department of Genetics, Instituto de Biociências,
Universidade Federal do Rio Grande do Sul 2. Department of
Psychiatry, Faculdade de Medicina, Universidade Federal do
Rio Grande do Sul 3. Adult ADHD Outpatient Clinic, Hospital
de Clínicas de Porto Alegre
* veronica.contini@gmail.com
Attention-deficit hyperactivity disorder (ADHD) is a highly
heritable disorder manifesting itself in symptoms of
inattention and/or hyperactivity/impulsivity that result in
impairment in multiple domains of adaptive functioning. The
pharmacotherapy is central in ADHD treatment and the main
pharmacological drug prescribed is methylphenidate
hydrochloride (MPH). Pharmacogenetics studies of MPH
response in ADHD have mainly focused on the 40-bp variable
number of tandem repeat (VNTR) in the 3’ untranslated region
(3’-UTR) of the DAT1. Most studies were performed in
children samples, and obtained conflicting findings. Only two
studies assessed the 3´VNTR in adult samples, one with
positive and the other with negative findings. In the present
study, we investigate three polymorphisms in the DAT1 gene
(3´VNTR; VNTR in intron 8 and -839 C>T), and their
possible role in the therapeutic response to MPH treatment in
a sample of 171 adults with ADHD. The diagnostic
procedures followed the DSM-IV criteria and the outcome
measures were the SNAP-IV subscales, applied at the
beginning and after the 30th day of treatment. The
polymorphisms were analyzed separately and considering
haplotypes comprising the 3´VNTR and the VNTR in intron 8.
No significant effects of any DAT1 polymorphisms or
haplotypes on the response to MPH were found. The current
report is the second to demonstrate no difference in MPH
response based upon DAT1 genotypes in adults with ADHD.
If there is a significant effect of DAT1 polymorphisms in adult
ADHD, this effect is likely to be very small.

15 FAMILY-BASED GENOME-WIDE ASSOCIATION
STUDY OF ATTENTION-DEFICIT/HYPERACTIVITY
DISORDER
E. Mick* (1), A. Todorov (2), S. Loo (3), X. Hu (4), B.
Dechairo (4), S. Hall (4), S. Nelson (3), C. Shtir (3), S.
Smalley (3), R. Todd (2), B. Neale (1), S. Faraone (5)
1. Massachusetts General Hospital 2. Washington University
School of Medicine 3. UCLA 4. Molecular Medicine, Pfizer
Inc. 5. SUNY Upstate Medical University
* emick1@partners.org
Genes likely play a substantial role in the etiology of
attention-deficit hyperactivity disorder (ADHD) but the
genetic architecture of the disorders is unknown and prior
genome-wide association studies have not identified a
genome-wide significant association. We have conducted a
third, independent multi-site GWAS of DSM-IV-TR ADHD
using the Illumina Human1Mand Human1M-Duo BeadChip
platforms. After applying quality control filters association
with ADHD was tested with 835,136 SNPs in 735 DSM-IV
ADHD trios from in 733 families. Our smallest p-value
(6.7E-07) did not reach the threshold for genome-wide
statistical significance (5.0E-08) but one of the 20 most
significant associations was located in a candidate gene of
interest for ADHD, (SLC9A9, rs9810857, p=6.4E-6). We also
conducted gene-based tests of candidate genes identified in the
literature and found additional evidence of association with
SLC9A9. We and our colleagues in the Psychiatric GWAS
Consortium are working to pool together GWAS samples to
establish the large data sets needed to follow-up on these
results and to identify genes for ADHD and other disorders.
16 ATTACHMENT DIFFICULTIES IN CHILDREN
WITH ATTENTION DEFICIT HYPERACTIVITY
DISORDER – A PHENOTYPE ANALYSIS STUDY
FROM THE INTERNATIONAL MULTICENTRE
ADHD GENETICS STUDY
A. Mulligan* (1), F. Motala (2), R. Anney (3), M. Gill (3)
1. University College Dublin 2. Mater Misericordiae
University Hospital 3. Trinity College Dublin
* aisling.mulligan@ucd.ie
Introduction: Children with attachment difficulties such as
reactive attachment disorder may present with hyperactivity.
This study tested the hypothesis that attachment difficulties
may occur in ADHD and may exacerbate symptoms of
ADHD. Aims: (1) To measure attachment difficulties in
children with ADHD and ascertain if children with ADHD and
attachment difficulties have more severe symptoms of ADHD
than those without attachment difficulties. (2) To ascertain if
there is an association between disorders comorbid to ADHD
and attachment difficulties in ADHD. Methods:Attachment
difficulties were measured for 966 children with ADHD,
combined type participating in the International Multicentre
ADHD Genetics study (IMAGE), using questions from the
Parental Account of Children’s Symptoms (PACS)
semi-structured interview. Diagnoses of oppositional defiant
disorder (ODD), conduct disorder (CD) and of anxiety
disorder were generated using the PACS. Current symptoms
of ADHD and of oppositional behaviour were measured using
the Conners’ parent and teacher rating scales. The group was
divided into those with no attachment difficulties and those
with some attachment difficulties, and ADHD symptom
severity was compared in each group. Attachment symptoms
were compared in those with and without comobid CD, ODD,
and anxiety disorder. Results: Parents of children with ADHD
and attachment difficulties (N=432) noted slightly more severe
symptoms of ADHD (mean Conners’ score = 79.07 vs. mean
Conners’ score = 75.77, p

17 FAMILY-BASED COPY NUMBER VARIATION
ASSOCIATION WITH ATTENTION-DEFICIT
HYPERACTIVITY DISORDER
C. Shtir* (1), S. Smalley (1), E. Mick (2), A. Todorov (3), B.
Dechairo (4), S. Faraone (3), S. Hall (4), S. Loo (1), J.
McCracken (1), J. MvGough (1), B. Neale (3), R. Todd (3), S.
Nelson (1)
1. University of California Los Angeles 2. Harvard Medical
School 3. Washington University 4. Pfizer Inc
* cshtir@mednet.ucla.edu
Several family and twin-based studies explored the genetic
landscape attributed with risk of developing attention-deficit
hyperactivity disorder (ADHD). However, major risk factors
are yet to be defined. Despite strong heritability, the complex
etiology of ADHD indicates that rare structural variants may
play a determinant role. We present a family-based
genome-wide copy number variation (CNV) screen followed
by CNV association tests, with the purpose of identifying
inherited and de novo ADHD-associated structural variants.
To our knowledge this is the second, yet largest ADHD study
characterizing effects of CNVs. A total of 733 trios
ascertained through the University of California at Los
Angeles, Washington University at St.Louis, and
Massachusetts General Hospital were analyzed for excess
transmission of CNVs and de novo mutations. Children
between 6-17 years old were diagnosed according to the
DSM-IV-TR criteria. UCLA trios were genotyped on the
Illumina Human 1M-Duo bead array, while WASH-U and
MGH samples were genotyped on the Illumina Human1M
bead array. Normalized logR Ratios of total SNP signal
intensities, quantile normalization and eigenstrat-based
principal component analyses were used to eliminate sample
and batch effects. Hidden-Markov-Model derived algorithms
were employed for detection of CNVs. Associations of
structural variants with ADHD were assessed through linear
regression models and Mann Whitney tests. We observe
evidence for CNV association with ADHD for genes involved
in neurological disorders and neurodevelopment pathways, for
transcription factors previously reported to be susceptible for
ADHD, and for a set of putative genes that may play an
additional role in the biogenesis of ADHD.
18 POSTNATAL EXPOSURE TO PCB153 ALTERS
CATECHOLAMINE AND SECOND MESSENGER
SIGNALING IN RATS: IMPLICATIONS FOR ADHD
T. Das Banerjee* (1), F. Middelton (1), E. Borgå Johansen
(2), T. Sagvolden (2), S. Faraone (1)
1. SUNY Upstate Medical university 2. University of Oslo
* dast@upstate.edu
ADHD is a neurobehavioral disorder with both genetic and
environmental components. PCB153 is one of the most
commonly detected polychlorinated biphenyl congeners in
human milk. Studies have shown that PCB153-exposed male
rats exhibit hyperactivity, a characteristic behavioral symptom
of ADHD. In this study we wanted to investigate the
molecular mechanism by which PCB153 induces ADHD-like
symptoms. The study was conducted in Wistar Kyoto (WKY)
male and female rats dosed via gavage with corn oil vehicle, 3
mg/kg b.w. of PCB153 from PND11-13. Brains were
harvested from the experimental and control animals at
PND65. For microarray screening, RNA from four dorsal
striatum samples was obtained per treatment group per gender,
with a total of 16 samples. RNA was processed using the
recommended Affymetrix protocol and hybridized to the
GeneChip Rat Gene 1.0 ST array. Gene-level as well as
exon-level analyses were performed for both males and
females and with them combined (in a 2 way ANOVA). Our
results show that there are major disruptions of catecholamine
and second messenger signaling in the brains of male and
female rats exposed to PCB153. These changes appear to be
gender specific. Altogether, the data suggests that postnatal
exposure to PCB153 significantly alters brain circuits involved
in ADHD.

19 NO EXCESS RATES OF CNV IN MALES
COMPARED TO FEMALES IN
NEURODEVELOPMENTAL DISORDERS AND
CONTROL INDIVIDUALS
I. Zaharieva* (1), A. Martin (1), K. Langley (1), C. Davies
(1), E. Evans (1), S. Syed (1), R. Roberts (1), K.
Mantripragada (1), N. Buttigieg (1), D. Grozeva (1), G. Kirov
(1), M. O'Donovan (1), M. Owen (1), N. Williams (1), A.
Thapar (1)
1. Cardiff University, MRC Centre for Neuropsychiatric
Genetics and Genomics
* zaharievait@cardiff.ac.uk
Recent studies implicate rare, large copy number variants in
neurodevelopmental disorders such as schizophrenia, autism
and attention deficit hyperactivity disorder (ADHD). Given
the fact that neurodevelopmental disorders more commonly
affect males, we wanted to investigate whether rare,
large-scale copy number variants (CNV) (greater than100 kb)
have higher rates in males compared to females. We used
three datasets for the analysis: a dataset of 316 ADHD male
patients and 50 ADHD female patients, a set of 314
schizophrenia male patients and 156 schizophrenia female
patients and a control set of 535 males and 512 females from
1958 birth cohort. No statistically significant difference was
observed when the total number of CNVs greater than 100 kb
was compared between males and females in each dataset. The
male to female ratio and p-values for each dataset are: ADHD
male/female ratio=1.1, p=0.66; Schizophrenia male/female
ratio=1.17, p=0.28; Controls male/female ratio=1.19, p=0.1.
Furthermore, we saw no significant difference after stratifying
the CNVs according to size. The minimum p-value observed
is 0.07 in controls for the size range 100kb to 500kb
(male/female ratio=1.23). In conclusion, our results show no
evidence that males have an increased burden of CNVs
compared to females in either ADHD or schizophrenia, and
the rates are very similar to those in normal controls.
20 ASSOCIATION OF DRD4 WITH CHILDHOOD
ADHD COMORBIDITY IN WOMEN WITH BULIMIA
NERVOSA
Z. Yilmaz* (1), A. Kaplan (1), R. Levitan (1), J. Kennedy (1)
1. University of Toronto
* zeynep.yilmaz@utoronto.ca
Purpose: Bulimia nervosa (BN) is a psychiatric disorder that
predominantly affects women, and is characterized by regular
binge eating, purging and characteristic psychopathology. Past
research has shown that a proportion of patients with BN
report a history of attention deficit/hyperactivity disorder
(ADHD), and the dopaminergic genes, especially the
dopamine receptor D4 (DRD4), have been associated
separately with both BN and ADHD. The purpose of this
study is to explore the possible role of DRD4 in predicting
ADHD comorbidity in women with BN. Methods: 81 women
with current or past BN purging subtype were genotyped for
the presence or absence of the hypofunctional 2-repeat
and 7-repeat alleles of DRD4. Patients also completed the
Wender Utah Rating Scale (WURS) for the assessment of
childhood ADHD history and the Brown Adult ADD Scale for
current ADHD symptoms. Results: The presence either the
2-repeat or 7-repeat alleles of DRD4 was associated with
childhood ADHD in BN patients, as assessed by the WURS.
There was no relationship between the Brown scores and the
DRD4 genotype. Conclusion: The pathophysiology of both
BN and ADHD may in part be related to an underlying
hypodopaminergic state, and these finding may have
implications for treatment, especially with dopaminergic
agents, for BN patients with a childhood history of ADHD.

21 A CIS-ACTING POLYMORPHISM IN SLC9A9 IS
NOT ASSOCIATED WITH ADHD IN AN IRISH
SAMPLE.
M. Hill* (1), Z. Hawi (2), M. Gill (2), R. Anney (2)
1. Centre for the Cellular Basis of Behaviour, Department of
Neuroscience, The James Black Centre, Institute of
Psychiatry, Kings College London, 125 Coldharbour Lane,
London, SE5 9NU, UK 2. Neuropsychiatric Genetics
Research Group, Department of Psychiatry, Trinity College
Dublin, Ireland
* matthew.hill@kcl.ac.uk
Introduction: Attention-deficit hyperactivity disorder (ADHD)
is a common neuropsychiatric disorder with a strong genetic
component. A recent genome-wide association study
implicates SLC9A9 as a potential susceptibility locus. The
nominally associated polymorphisms reside within non-coding
regions of the gene and are thus hypothesised to confer
vulnerability via altering gene expression. This study aimed to
identify cis-acting variants in this promising candidate gene
and test for their association with ADHD in an Irish sample.
Methods: Using RNA from the HapMap CEU lymphoblasts
we measured allelic expressing imbalance (AEI) of the
SLC9A9 transcript using a transcribed single nucleotide
polymorphism (SNP). Transmission dysequilibrium testing in
an ADHD parent-child sample was performed to test for
association with ADHD. Results: Moderate imbalance of the
SLC9A9 transcript was observed in 7 of the 45 individuals
suitable for investigation. Correlation between AEI and ~1000
SNPs across the gene and flanking regions revealed a single
SNP that was highly correlated with imbalance and remained
significant after correction for multiple testing. Subsequent
association testing revealed that this SNP was not associated
with ADHD in an Irish sample. Conclusion: This study has
identified moderate and infrequent allelic expression
imbalance of the SLC9A9 transcript in lymphoblasts indicting
the presence of cis-acting variants. A likely cis-acting variant
identified by this screen was not associated with ADHD. The
role of this SNP in other diseases, e.g. autism and
Alzheimer’s, in which SLC9A9 is implicated is of future
interest.
290 BIPOLAR DISORDER CANDIDATE
REGULATORY MUTATIONS IN NR2E1
FUNCTIONALLY EVALUATED IN VIVO IN MICE
J. Schmouth* (1), R. Bonaguro (1), C. de Leeuw (1), L.
Dreolini (2)
1. Centre for Molecular Medicine and Therapeutics, Child &
Family Research Institute, University of British Columbia,
Department of Genetics 2. Canada's Michael Smith Genome
Sciences Centre, British Columbia Cancer Agency,
Vancouver, Canada
Background: NR2E1 is a gene coding an orphan nuclear
receptor expressed in vertebrate forebrain and in the adult
brain. Previous case-control studies in the Simpson laboratory
associated NR2E1 with bipolar disorder and resequencing of
NR2E1 revealed 14 novel candidate regulatory mutations in
patients suffering from either bipolar disorder or cortical
malformation (microcephaly). Adult mice lacking Nr2e1
(‘Fierce’ mice) display hyperactivity, increased aggression,
and altered neurogenesis. A transgenic “rescue” study using
random-insertion mice harboring multiple copies of the human
NR2E1 gene on the Nr2e1-null background has shown that
NR2E1 is sufficient to correct the fierce phenotype.
Hypothesis: Candidate mutations in human NR2E1 regulatory
regions will cause brain and behaviour disorders in Nr2e1-null
mice. Material and methods: Five mouse models harboring
human NR2E1 BAC DNA, introduced in the genome as a
single copy, using the Hprt1 locus are being generated. These
will be bred onto the fierce background and assessed for
rescue of behavioural and histological phenotypes. Results:
We have generated the positive control (wild-type) mouse
strain, which is currently undergoing breeding to the fierce
background. One variant sequence g.2078G>C has generated
chimeric animals and the negative control (deletion allele) has
been generated and been electroporated in embryonic stem
cells (ESCs). Conclusion: This work may demonstrate that the
candidate mutations identified in regulatory regions of human
NR2E1 are capable of causing brain and behaviour disorders
in mice. This will support NR2E1 as a new drug target, and
the role of genetic testing as part of diagnosis and treatment of
bipolar disorder.

292 DOPAMINE D4 RECEPTOR GENE: POSSIBLE
INFLUENCE ON ATTENTION DEFICIT
HYPERACTIVITY DISORDER IN BRAZILIAN
POPULATION
G. Akutagava-Martins (1), G. Ferraz (1), J. Genro (1), G.
Polanczyk (2), C. Zeni (3), M. Schmitz (3), L. Rohde (3), M.
Hutz (1), T. Roman* (1)
1. Department of Genetics, Federal University of Rio Grande
do Sul, Brazil 2. Department of Psychology and Neuroscience,
Duke University, USA 3. Department of Psychiatry and Legal
Medicine, Federal University of Rio Grande do Sul, Brazil
The dopamine D4 receptor gene (DRD4) is one of the most
investigated genes in Attention deficit/hyperactivity disorder
(ADHD) and has already been accepted as a susceptibility
gene. The aim of present study was to search for a possible
association between ADHD and the 120 bp tandem
duplication of promoter region, the SNPs -616C>G (rs747302)
and -521C>T (rs1800955) and the 48 bp VNTR of DRD4 gene
in a Brazilian sample composed by 488 ADHD children and
adolescents, diagnosed according to DSM-IV criteria, and
their biological parents. The 120 bp tandem duplication and
the 48 bp VNTR were genotyped by PCR, while the SNPs
-616C>G and -521C>T were genotyped by PCR-RFLP. The
possibility of linkage disequilibrium among the studied
polymorphisms was tested using MLocus software. The
hypothesis of association was verified using FBAT software.
There was no evidence of association between each
polymorphism and ADHD for the whole sample (P values
ranging from 0.200 to 0.974). However, when the analysis was
restricted to families where the proband presented the
combined type of the disorder, the VNTR 2R allele was
preferentially not transmited (P=0.033). Haplotype analyses
did not show any association (P values ranging from 0.063 to
0.977). The supposed protective effect of 2R allele observed
herein is intriguing. This result must be interpreted cautiously
and investigated through other approaches, as dimensional
analyses. It is also possible that the findings, divergent from
the literature, are due to DRD4 structural complexity, which
should be understood to better characterize its association with
ADHD.

EARLY CAREER INVESTIGATOR TRACK:
ALTERNATIVE PHENOTYPES, GENE-
GENE, AND GENE-ENVIRONMENT
INTERACTION
ECI 1 ASSOCIATION OF CAROTENOID
ANTIOXIDANT AND SCHIZOPHRENIA USING
NON-INVASIVE MEASUREMENT
T. Chow (1), S. Tee (1), H. Loh (1), P. Tang (1), S. Soon (1)
1. Universiti Tunku Abdul Rahman
During stress, abnormally high neuronal activities in human
brain would trigger excessive free radicals as part of the body
immune response. This impairs antioxidant defense system
and causes detrimental effects on signal transduction.
Antioxidants are hypothesized to counteract oxidative stress
and thus are suspected to be involved in stress-related
disorders including schizophrenia. Carotenoids serve as a
powerful free radical-neutralizing antioxidant which is
absorbed in human plasma and tissue, therefore providing
reliable indicator of a person’s overall antioxidant level. This
study aims to investigate the possible relationship between
carotenoid antioxidant level and schizophrenia. A total of 524
schizophrenic subjects and 289 healthy control subjects were
recruited. Subject skin carotenoid score were determined using
non-invasive Raman spectroscopy technique that measures
stable carotenoids in the human skin. Statistical analyses
compared carotenoid score: (i) between patients and controls
in different age and gender, and (ii) among patients with
different subtypes, medications, and duration of illness. The
results showed significant (p

at TTC12 and CHRNA3 appears to be additive. TTC12 seems
to influence mainly initiation of use in adolescence. In
contrast, genetic variation at CHRNA3 appears to be mainly
involved in the transition towards regular/heavy use in
adulthood.
ECI 3 ASSOCIATION OF CHROMOSOME 20 LOCI
WITH CATEGORICAL DIAGNOSES AND CLINICAL
DIMENSIONS OF SCHIZOPHRENIA IN THE IRISH
STUDY OF HIGH DENSITY SCHIZOPHRENIA
FAMILIES
T. Bigdeli* (1), B. Maher (1, 2), Z. Zhao (1, 2), E. van den
Oord (3), B. Webb (3), R. Amdur (4), S. Bergen (1), F. O'Neill
(5), D. Walsh (6), B. Riley (1, 2), K. Kendler (1, 2)
1. Department of Human and Molecular Genetics, Virginia
Institute for Psychiatric and Behavioral Genetics, Virginia
Commonwealth University, Richmond, VA, USA 2.
Department of Psychiatry, Virginia Institute for Psychiatric
and Behavioral Genetics, Virginia Commonwealth University,
Richmond, VA, USA 3. Virginia Institute for Psychiatric and
Behavioral Genetics, Center for Biomarker Research and
Personalized Medicine, Virginia Commonwealth University,
Richmond, VA, USA 4. Mental Health Service Line,
Washington VA Medical Center, Washington, DC 5.
Department of Psychiatry, Queens University, Belfast, UK 6.
The Health Research Board, Dublin, Ireland
* bigdelitb@vcu.edu
Background: Prior genomewide scans of schizophrenia
support evidence of linkage to regions of chromosome 20.
However, association analyses have yet to provide support for
any etiologically relevant variants. Methods: We analyzed
2988 LD-tagging single nucleotide polymorphisms (SNPs) in
327 genes on chromosome 20, to test for association with
schizophrenia in 270 Irish high-density families (ISHDSF,
N=270 families, 1408 subjects). These SNPs were genotyped
using an Illumina iSelect genotyping array which employs the
Infinium assay. Given a previous report of novel linkage with
chromosome 20p using latent classes of psychotic illness,
association analysis was also conducted for each of five
factor-derived scores based on the Operational Criteria
Checklist for Psychotic Illness (delusions, hallucinations,
mania, depression, and negative symptoms). Tests of
association were conducted using the PDTPHASE and
QPDTPHASE packages of UNPHASED. Results: While no
single variant was significant after Bonferroni-correction,
initial gene-dropping simulations identified loci which
exceeded empirical significance criteria for minimum
genewise P value or the truncated product of P values. In
particular, TOX2 shows association with both intermediate
and broad diagnoses of schizophrenia. Additionally,
R3HDML and C20orf39 appear to be associated with
depressive symptoms of schizophrenia. Conclusions:
Preliminary results overall provide evidence that chromosome
20 may harbor schizophrenia susceptibility or modifier loci.
Ongoing gene-dropping analyses aim to assess the empiric
significance of these associations.
ECI 4 EFFECTS OF MEDICATION ON
MONOAMINE-RELATED GENE EXPRESSION IN
BLOOD OF CHILDREN WITH TOURETTE
SYNDROME
I. Liao* (1), L. Lit (1), B. Corbett (1), D. Gilbert (2), S. Bunge
(3), F. Sharp (1)
1. University of California, Davis 2. University of Cincinnati
3. University of California, Berkeley
* isaacliao@gmail.com
Tourette syndrome (TS), a highly heritable
neurodevelopmental disorder of unknown etiology resulting in
motor and verbal tics, is frequently treated with
psychopharmacological agents affecting monoamine
neurotransmission, such as dopamine receptor antagonists.
Previous studies have demonstrated differences in gene
expression in blood between TS and controls; however, some
of these differences might reflect medication effects. To
address this, we examined gene expression in the peripheral
blood of 28 medicated TS subjects (MED) and 26
unmedicated TS subjects (UNMED) using whole-genome
Affymetrix microarrays. Expression of the D2 dopamine
receptor gene (DRD2) was correlated with tic severity in MED
but not UNMED, suggesting an effect of medication on
DRD2. Expression of the epsilon subunit of the GABA
receptor (GABRE), which results in insensitivity to
anesthetics and increases the opening probability of the
GABA receptor, was negatively correlated with tic severity in
UNMED but not MED. In addition, expression of
phenylethanolamine N-methyltransferase (PNMT), an enzyme
responsible for the synthesis of epinephrine from
norepinephrine (NE), was positively correlated with tic
severity in UNMED but not MED. Because GABRE is found
on NE-ergic neurons in the locus coeruleus, and the locus
coeruleus receives PNMT-rich projections, these findings
support current pharmacological clinical data that suggest an
abnormality in locus coeruleus/NE circuits in TS. In addition,
these findings demonstrate the effects of medication on blood
gene expression in TS.

ECI 5 ANALYSIS OF DAT1 AND 5HTT GENES ADN
PSYCHOSOCIAL ADVERSITIES IN ADOLESCENT
INHABITANTS OF MEXICO CITY
G. Martinez Levy* (1), M. Cardenas-Godinez (1), M.
Briones Velasco (1), A. Gomez-Sanchez (1), E. Mendez (1),
B. Corina (1)
1. Instituto Nacional De Psiquiatria Ramon De La Fuente
Muñiz
* gaaml82@yahoo.com.mx
Attention Deficit Hyperactivity Disorder (ADHD) is a
clinically multifactorial mental disorder. Its etiology is
unknown, however a complex interplay between genetic and
environmental factors has been proposed. Three thousand and
five subjects (12-18 years old) inhabitants of the metropolitan
area of Mexico City, were interviewed face to face using the
Adolescent-CIDI-CAPI, which generates a psychiatric
diagnosis based on the DSM IV-R and ICD-10 criteria.
Psychosocial adversity information was also gathered from
this survey. Three hundred and two individual fulfill diagnosis
criteria for ADHD, with 252 cases that agreed to give a saliva
sample. They were typed for the LPR localized in the
promoter region of 5HTT and the VNTR of the 5 region of the
DAT1 gene, and compared with 284 DNA samples randomly
chosen of the 833 participants who did not fulfill diagnostic
criteria for any psychiatric disorder and gave saliva sample.
Physical abuse, negligence, substance use and criminal
conduct in parents as well as family violence were adversities
clearly associated with the diagnosis of ADHD. No
differences in genotypic or allelic frequencies for these
particular variants were observed between cases and controls.
Evaluations of the interaction among these molecular and
psychosocial variables, as well as the analysis of other
candidate genes are in progress.
ECI 6 MATERNAL SMOKING DURING PREGNANCY,
OFFSPRING BEHAVIORAL DISORDERS, AND THE
SEROTONIN 1B RECEPTOR
A. Talati* (1), S. Hamilton (2), P. Wickramaratne (1), S.
Hodge (1), M. Weissman (1)
1. Columbia University 2. University of California San Diego
* at2071@columbia.edu
Background: Smoking by mothers during pregnancy is
associated with a number of adverse physiological and
behavioral outcomes among their offspring, including
premature birth, lower birth-weight, cognitive impairment, and
behavioral and substance use disorders. We present here
findings on the long-term effects of maternal smoking
exposure on offspring, and further investigate genetic
underpinnings of the association. Method: Mothers and
offspring were interviewed at multiple waves spanning more
than twenty years. Psychiatric diagnoses were determined at
each wave using the age-appropriate version of the Schedule
for Affective Disorders and Schizophrenia (SADS). Smoking
during pregnancy was ascertained by maternal self-report;
offspring were classified based on whether or not their mother
smoked ≥10 cigarettes per day, nearly every day. Final
diagnoses of mothers and offspring were made independently,
using the best estimate procedure, and blind to maternal
smoking and previous child and maternal assessments. Single
nucleotide polymorphisms (SNPs) were tested within the
serotonin transporter (SLC6A4) and 1B (HTR1B) receptor,
and the monoamine oxidase A variable nucleotide repeat
region (MAOAVNTR). Results: After adjusting for multiple
potential confounders, maternal smoking during pregnancy
was associated with a 3-fold increase in drug and alcohol use
disorders among female, and a two-fold increase in conduct
disorder among male, offspring. One SNP rs6298, located
within the coding region of HTR1B was associated with a
five-fold increase in AUD and a nine-fold increase in CD.
When the association between smoke exposure and offspring
psychopathology was further stratified by the genotype at the
above polymorphism, exposure to smoking was associated
with CD among offspring with TT but not CC/CT genotypes.
Conclusion: Our data show that HTR1B is associated with
conduct and alcohol use disorders, and suggest that HTR1B
may further moderate the impact of exposure to maternal
prenatal smoking on offspring psychopathology.

ANIMAL MODELS
22 THE DOG AS A GENETIC MODEL FOR SOCIAL
BEHAVIORS: PRELIMINARY INVESTIGATION OF
SOCIAL INTERACTIVE BEHAVIORS IN DOGS
USING GENOME WIDE ANALYSIS
L. Lit* (1), S. Boyd (2), D. Hessl (1), D. Bannasch (3)
1. Dept of Psychiatry & M.I.N.D. Institute, University of
California Davis 2. Chief, Section of Genetics; Children's
Miracle Network Endowed Chair; M.I.N.D. Institute,
University California Davis 3. Dept of Population Health &
Reproduction, School of Veterinary Medicine, University of
California Davis
* llit@ucdavis.edu
Currently, there are no animal models that can provide insight
into the genetic underpinnings of normal social behaviors that
are impaired in neurodevelopmental disorders. Social
interactive behaviors between domestic dogs (Canis
familiaris) and humans have been well documented
experimentally. It has been hypothesized that a limited subset
of wild canids originally displayed the social characteristics
necessary to interact with humans, ultimately resulting in
domestication. This suggests that some genes contributing to
social interactive behaviors might predate breed formation,
and that these genes would be associated with social behaviors
irrespective of breed. We asked owners of 14 dogs (1 Basset
Hound, 1 Black Russian Terrier, 2 Dalmatians, 1 Petit Basset
Griffon Vendeen, 7 Nova Scotia Duck Tolling Retrievers, and
2 mixed breed dogs) to complete surveys comprising owner
report of social interactive behaviors observed in their dogs.
Subscales representing initiation of reciprocal social behaviors
(INIT), response to social interactions with humans (RSPNS),
communication with humans (COMM), and attention (ATT)
were derived from responses using factor analysis.
Genome-wide SNP data for these dogs was generated using
127K Affymetrix canine SNP arrays. Using subscales as
input, we performed genome-wide quantitative trait
association analysis with 10,000 permutations to determine
SNPs associated with each subscale. SNPs were identified
that corresponded to genes or regions homologous to those in
humans associated with autism, ADHD, and schizophrenia.
This contributes to the validity of the domestic dog as a model
to investigate naturally occurring variation in social behaviors
impaired in neurodevelopmental disorders in humans.
23 SUSCEPTIBILITY TO ANTIPSYCHOTIC-INDUCED
VACUOUS CHEWING MOVEMENTS AND OTHER
EXTRAPYRAMIDAL SYMPTOMS ARE HIGHLY
HERITABLE TRAITS IN MICE
J. Crowley* (1), C. Quackenbush (1), A. Pratt (1), D. Adkins
(2), E. van den Oord, M. Bogue (3), H. McLeod (1), P.
Sullivan (1)
1. UNC Chapel Hill 2. VCU 3. The Jackson Laboratory
* crowley@unc.edu
Around 50% of patients with schizophrenia discontinue
assigned treatments due to intolerable adverse drug reactions
(ADRs), but there are no clinically useful tests to predict
individual risk. The primary ADRs limiting the utility of
typical antipsychotic drugs are extrapyramidal side effects
(EPS), most notably tardive dyskinesia (TD), characterized by
involuntary orofacial movements. The confident identification
of TD susceptibility genes in human patients has proven to be
very difficult and it remains unclear if TD susceptibility is
sufficiently heritable to expect the identification of useful
genetic predictors. To address these limitations, we have used
a genetically diverse panel of mice to calculate the heritability
of antipsychotic-induced EPS. A total of 18 inbred mouse
strains (N = 5 mice per strain) were chronically treated with
haloperidol (3 mg/kg/day) for 120 days and monitored for the
development of vacuous chewing movements (VCMs; the
mouse analog of TD) and other movement phenotypes derived
from open field activity and an inclined screen test. These
longitudinal data allowed us to calculate the heritability of the
over-time response trajectories induced by haloperidol
treatment (ratio of strain-level variance to strain-level +
mouse-level variance). Every movement phenotype examined
showed an across-time drug response heritability >50% and
VCMs demonstrated an 81% heritability. Furthermore,
confirmatory factor analysis revealed two significant factors
underlying the movement response trajectories, with one
factor explaining most of the variance in the locomotor
activity response trajectories and the other primarily
explaining the orofacial movement response trajectories.
These data suggest that mapping of susceptibility alleles for
EPS is a worthwhile endeavor. To our knowledge, this is the
first demonstration that VCMs, the murine analog of TD, is a
highly heritable mammalian trait.

24 EFFECTS OF PRENATAL NICOTINE EXSPOSURE
ON DOPAMINERGIC GENE EXPRESSION AND
METHYLATION STATUS
N. Ilott* (1), J. Mill (1), P. Asherson (1), I. Stolerman (2), L.
Bizarro (3)
1. MRC SGDP Research Centre, Institute of Psychiatry, Kings
College, London 2. Section of Behavioural Pharmacology,
Institute of Psychiatry, King's College London 3.
Universidade Federal Do Rio Grande do Sul, Departamento de
Psicologia do Desenvolvimento e da Personalidade, Instituto
de Psicologia, Rua Ramiro Barcellos 2600, Porto Alegre - -
RS, Brasil
* nicholas.ilott@iop.kcl.ac.uk
Smoking during pregnancy (SDP) is an important risk factor
for a number of developmental conditions including sudden
infant death syndrome (SIDS) and behavioural abnormalities.
Human studies have identified SDP as contributing to the
development of externalizing behaviours such as Attention
Deficit Hyperactivity Disorder (ADHD) and Antisocial
Behaviour (ASB) although the causal role of tobacco exposure
remains unclear. Animal studies have provided an insight into
the behavioural consequences of gestational nicotine with
suggested associations with increased locomotor activity,
heightened anxiety as well as learning deficits. Molecular
mechanisms underlying these behavioural consequences have
been considered, with evidence suggesting long-lasting effects
on nicotinic acetylcholine receptor (nAchR) subunit
expression and neurotransmitter signaling. Here we investigate
altered regulation of dopamine system genes because of the
central role of dopaminergic transmission in ADHD. We
studied expression and methylation patterns of five
dopaminergic genes in the striatum and frontal cortex of adult
rats prenatally exposed to nicotine. We found no major
differences in either mRNA expression or promoter
methylation for any of the genes investigated, although there
was a small but significant increase in dopamine receptor D5
(DRD5) mRNA expression in striatum of exposed animals
compared to controls. Therefore we report no major effects of
gestational nicotine on the expression or methylation of the
genes we have investigated. This work is being extended to an
investigation at the level of the transcriptome and methylome
to provide an unbiased approach for looking at gene regulation
by gestational nicotine.
25 BRAIN GENE EXPRESSION IN MICE
HYPOMORPHIC FOR NEUREGULIN 1 (NRG1) AND
THE EFFECTS OF THE ATYPICAL ANTIPSYCOTIC
CLOZAPINE
A. Byrnes* (1), J. Crowley (2), T. Konneker (2), J. Dackor
(2), F. Wright (1), E. Anton (3), P. Sullivan (2)
1. Department of Biostatistics, University of North Carolina at
Chapel Hill, NC 2. Department of Genetics, University of
North Carolina at Chapel Hill, NC 3. Department of Cell and
Molecular Physiology, University of North Carolina at Chapel
Hill, NC
* abyrnes@bios.unc.edu
Schizophrenia (SCZ) is a severe and highly heritable
psychiatric disorder for which neuregulin 1 (NRG1) may play
an etiological role. Mice hypomorphic for Nrg1 have been
shown to exhibit SCZ-like characteristics that are ameliorated
with clozapine and represent a potential animal model for
SCZ. The study aims to explore the effects of a Nrg1 mutation
on forebrain gene expression and the effects of clozapine. We
compared gene expression in forebrain from 8 Nrg1
hypomorphic and 8 wild type mice using the Illumina and
Affymetrix expression assays treated with vehicle along with
8 Nrg1 hypomorphic and 8 wild type mice treated with the
atypical antipsychotic clozapine. Statistical analyses
contrasted the effects of strain (Nrg1 hypomorph vs wild type)
and drug (vehicle vs clozapine). As expected, we found that
Nrg1 expression was significantly higher in wild type mice as
compared to hypomorphic mice. Other differentially expressed
transcripts include ADP-ribosylation factor-like 3 (Arl3) and
Hermansky-Pudlak syndrome 1 homolog (Hps1).
Transcription of mitochondrial tryptophanyl tRNA synthetase
2 (Wars2) and interleukin-1 receptor-associated kinase (Irak)
appear to be altered by treatment with clozapine. Irak also
showed significant interaction effects, as did member RAS
oncogene family (Rab). Numerous pathways were also
significant in these analyses. These include immune function
and response to stimulus and olfactory receptors which
appears to have convergent validity with respect to recent SCZ
GWAS results.

26 THE KNOCKOUT MOUSE REPOSITORY
HTTP://WWW.KOMP.ORG/
R. O'Neill* (1), P. de Jong (2), K. Lloyd (3)
1. DCM, NCRR, NIH 2. Children's Oakland Research Institute
3. University of California, Davis
* oneillr@mail.nih.gov
Genome wide association studies (GWAS) and other
investigations of human psychiatric conditions are discovering
the association of specific phenotypes with various gene
alleles and single nucleotide polymorphisms (SNPs). In
followup experiments, knocking out one specific gene in an
animal model can determine the function of a gene suspected
of causing the human condition. More than 2,000 different
mouse Embryonic stem (ES) cell lines carrying specific gene
knockouts (KOs) can be obtained from the Knockout Mouse
Program (KOMP) Repository. In addition, KO vectors
useful for targeting recombination in ES cells, and KO mice,
are currently available. In 2011, ~8,500 such individual gene
KOs will be available from the KOMP repository.
http://www.komp.org/can be queried to see if an individual
investigator's gene of interest is already available, or to
register interest in a specific KO that will or could be made.
More than 100 of the 2,000 KOs currently available have
annotations in Online Mendelian Inheritance in Man. Several
vector constructs are used to make KOs, and conditional
vectors allow tissue-specific or cell-type-specific perturbations
within the nervous system. This is done by temporally or
spatially restricting expression of the KO vector phenotype via
combination with various patterns of Cre-recombinase
expression (>100 Cre-drivers from
http://www.credrivermice.org/). Nineteen Institutes and
Centers at NIH fund these efforts, with the repository located
at the University of California, Davis and the Children's
Oakland Research Institute; with major partners at the Sanger
Institute in the U.K.; Velocigene at Regeneron, Inc.; and the
Jackson Laboratory.
294 A RECENT SINE INSERTION CREATED A
COMT-OVEREXPRESSING, BEHAVIOUR
MODIFYING ALLELE IN MANY INBRED MOUSE
STRAINS.
R. Kember* (1), C. Fernandes (1), E. Tunbridge (2), L. Liu
(1), J. Payo-Cano (1), H. Lad (1), M. Parsons (1), L.
Schalkwyk (1)
1. Institute of Psychiatry, Kings College London 2.
Department of Psychiatry, University of Oxford
Comt is a key enzyme of neurotransmitter catabolism and a
perennial candidate gene for human psychiatric disorders. In
mouse it is located in a large genomic region of extremely low
variation among the classical inbred strains, with only four
known putative SNPS in 600 Kb. The strain C57BL/6J and
others including 129 (multiple substrains) have a B2 SINE
insertion in the 3' UTR which is not present in others
including DBA/2J and C3HeB/FeJ. A stringent association
test, using over 700 highly outbred mice with data from an
extensive behavioural battery, indicates that this insertion
allele is responsible for differences in behaviour related to
exploration and anxiety. Differences in the gene expression
level and in the activity of the enzyme itself (74% increase in
activity with the insertion) indicate a mechanism for these
behavioural effects. This finding robustly shows that a
relatively modest difference in Comt expression (comparable
to the human Val/Met polymorphism) can have demonstrable
phenotypic effects across behaviours in a human-like variety
of outbred genetic backgrounds.

ANXIETY DISORDERS
27 A PH SENSITIVE SODIUM CHANNEL IS A
POTENTIAL CANDIDATE GENE FOR PANIC
DISORDER
N. Gregersen* (1), H. Nørmølle Buttenschøn (2), M.
Nyegaard (1), H. Dahl (3), A. Hedemand (1), A. Suhl
Kristensen (2), D. Woldbye (4), S. Joensen (5), T. A. Kruse
(3), A. Børglum (1), O. Mors (2)
1. Inst. of Human Genetics, Aarhus University, Denmark 2.
Center for Psychiatric Research, Aarhus University Hospital,
Risskov, Denmark 3. Dept. of Clinical Biochemistry and
Genetics, University of Southern Denmark 4.
Neuropsychiatric Recearch Laboratory, University of
Copenhagen, Denmark 5. Dept. of Psychiatry, National
Hospital, Faroe Islands
* noomigregersen@mac.com
INTRODUCTION: A genome wide scan conducted on 13
patients with panic disorder, PD, from the isolated population
of the Faroe Islands, observed significant association with
chromosome 17p11.2. This chromosomal region contains the
pH sensitive sodium channel ACCN1. Markers within this
gene have shown to be significantly associated with PD. The
aim of current study was to replicate the findings on
chromosome 17 in a new Faroese PD sample and in an
outbred Danish sample of patients with PD and control
individuals. METHODS: We have genotyped 50tagSNPs in
the ACCN1 gene region using the Sequenom platform
(Sequenom, Inc.San Diego, USA) and the Lightcycler 480
Genotyping master (RocheApplied Science, Mannheim,
Germany). DNA from 14 patients with PD and 119 controls
was obtained from the Genetic Biobank of the Faroe Islands.
The Danish population consisted of 365 cases and 649 control
individuals. For statistical analysis we used PLINK
(https://gene.gram.au.dk/bcos/index.html). RESULTS: One of
the markers was significantly associated with PD in the new
Faroese sample (rs9906088: p=0.0268). In the combined
Faroese case-control sample consisting of 27 cases and 162
controls four SNP´s were significantly associated with PD
(p-values ranging from 0.008p to 0.0144). Three SNP´s were
significantly associated with PD in the Danish
case-controlsample (p-values ranging from 0.0002 to 0.0139).
DISCUSSION: These results indicate ACCN1 to be a
potential candidate gene for PD. However, further studies are
needed. Furthermore, we were not able to replicate the most
significantly associated marker from the previous study.
ACKNOWLEDGEMENTS: Genetic Biobank of the Faroes
for samples and the Lundbeck foundation for financing the
project.
28 G ALLELE CARRIERS AT 5HT1A HAVE AN
INCREASED RISK FOR MIXED ANXIETY AND
DEPRESSION
E. Molina (1), J. Cervilla (2), M. Rivera (3), B. Gutiérrez (1)
1. CIBERSAM UGR, Spain 2. CIBERSAM UGR, HU San
Cecilio, Spain 3. CIBERSAM UGR, Institute of Psychiatry
London
Serotonin 1A receptors are key regulators of serotonin activity
and their dys-regulation might be involved in the pathology of
major depression (MD) and generalized anxiety disorder
(GAD). Previous studies have yielded inconclusive results as
to whether the 5-HT1A receptor gene has a role in the
aetiology of MD and no study up to date had studied this
polymorphism on either pure MD or MD comorbid with
GAD. We aim to clarify the putative role of the C (-1019) G
polymorphism at the serotonin 1A receptor gene in the
aetiology of both MD and GAD and comorbid MD/GAD
states. DSM-IV MD and GAD diagnoses were ascertained
using the Composite International Diagnostic Interview and
the Primary Care Evaluation of Mental Disorders Patient
Health Questionary, respectively. 1059 sujects who took part
in the PREDICT-GENE study (1) were included for molecular
analyses using Sequenom platform. Carrying the G allele of
the C (-1019) G polymorphism was associated with MD (OR
= 1.67, 95%CI = 1.14 - 2.44, p = 0.008) but this association
became non-significant after adjusting by presence of GAD
(OR = 1.43, 95%CI = 0.958-2.141, p = 0.080). Similarly, the
C (-1019) G polymorphism was univariately associated with
GAD (Crude: OR = 2.54, 95%CI = 1.28-4.861, p = 0.003),
although adjusting by MD made results no longer significant
(OR =1.97, 95%CI = 0.991-3.910, p=0.05). However, we
found a solid significant association between carrying the G
allele and comorbid MD and GAD (OR =3.41, 95% CI =
1.444-8.048, p = 0.005) which remained robust and
statistically significant after adjusting by sex, age and family
history of psychological problems (OR =2.82, 95%CI =
1.177-6.772, p = 0.020). Our results suggest that the C (-1019)
G serotonin 1A polymorphism confers a risk for the frequent
clinical presentation of comorbid MD and GAD but not for
either of these disorders alone after adjusting by presence of
one another.

29 REPLICATION OF A GENOME-WIDE
ASSOCIATION STUDY OF PANIC DISORDER IN A
JAPANESE POPULATION
T. Otowa* (1), T. Minato (1), N. Sugaya (2), K. Inoue (3), T.
Shimada (1), Y. Kawamura (1), M. Tochigi (1), T. Umekage
(1), H. Tanii (4), T. Miyagawa (5), N. Nishida (5), K.
Tokunaga (5), Y. Okazaki (6), H. Kaiya (7), T. Sasaki (8)
1. Department of Neuropsychiatry, Graduate School of
Medicine, the University of Tokyo 2. Outpatient Clinic for
Anxiety Disorders, Akasaka Mental Clinic 3. Department of
Public Health, Fujita Health University School of Medicine 4.
Department of Neuropsychiatry, Graduate School of
Medicine, Mie University 5. Department of Human Genetics,
Graduate School of Medicine, the University of Tokyo 6.
Department of Neurology, Tokyo Metropolitan Matsuzawa
Hospital 7. Research Center for Panic Disorder, Nagoya
Mental Clinic 8. Office for Mental Health Support and
Graduate School of Education, the University of Tokyo
* totowa-psy@umin.ac.jp
Panic disorder (PD) is an anxiety disorder characterized by
recurrent and unexpected panic attacks, subsequent worry, and
phobic avoidance. Although a number of association and
linkage studies have been conducted, no gene has been
identified as a susceptibility locus. We previously conducted a
genome-wide association analysis of PD in 200 Japanese
patients and the same number of controls, using a 500K single
nucleotide polymorphisms (SNPs) chip. Here we report a
replication analysis of PD using the DigTag2 assay. DigTag2
assay is suitable for genotyping an intermediate number of
SNPs with high accuracy. The second stage sample consisted
of 558 Japanese patients and 566 controls. Thirty-two markers
were tested in a replication sample. As a result, no significant
association could be found after correction for multiple
testing. However, the difference was observed at the nominal
allele P-value < 0.05 for two SNPs (rs6733840 and rs132617).
Further studies on these variants with a larger sample size may
be worth testing to confirm the results.
30 GENETICS OF PANIC DISORDER: A
GENOME-WIDE ASSOCIATION STUDY
J. Schumacher* (1), C. Allgulander (2), E. Binder (3), J.
Deckert (4), K. Domschke (5), A. Erhardt (3), E. Eriksson (6),
J. Ioannidis (7), J. Kennedy (8), A. Kristensen (9), E. Maron
(10), A. Metspalu (10), O. Mors (9), J. Nurnberger (11), T.
Otowa (12), R. Philibert (13), A. Reif (4), M. Rietschel (14),
T. Sasaki (12), T. Schulze (1), D. Woldbye (15), F. McMahon
(1)
1. NIMH Bethesda 2. Karolinska Institute 3. MPI Munich 4.
Univ. Wuerzburg 5. Univ. Muenster 6. Univ. Goteborg 7.
Univ. Ioannina 8. Univ. Toronto 9. Univ. Aarhus 10. Univ.
Tartu 11. Univ. Indiana 12. Univ. Tokyo 13. Univ. Iowa 14.
Univ. Heidelberg 15. Univ. Copenhagen
* schumacherj@mail.nih.gov
Panic disorder (PD) is a severe, heritable condition affecting
about two percent of the population. The mode of inheritance
is complex and involves multiple contributing genes, each of
small to moderate effect. Although genetic linkage has been
reported to a number of chromosomal regions, no linkage
finding has been replicated consistently throughout all studies.
In addition, all candidate gene association studies applied to
PD so far have failed to deliver definitive results. There is
increasing evidence that genome-wide association (GWA)
studies represent a promising approach to the identification of
genes involved in complex disorders, such as PD. The Panic
International Consortium (PANIC) was established as a
collaborative approach involving most of the leading
international PD research groups (from the Universities of
Aarhus, Copenhagen, Goteborg, Heidelberg, Indiana, Iowa,
Münster, Tartu, Tokyo, Toronto, Würzburg, the Karolinska
Institute in Stockholm, the MPI in Munich, and the NIMH),
with statistical advice from John Ioannidis (University of
Ionnina). The initial goal was to complete a GWA on one of
the largest PD samples. In total, the PANIC sample consists of
>2,000 patients and > 2,000 controls from two different
populations, which were collected at 12 different research
sites. The GWA results on the full PANIC sample will be
presented. The identified genes may represent promising
targets for functional studies aimed at improved diagnosis and
treatment.

AUTISM
31 SOCIAL RESPONSIVENESS SCALE:
STANDARDIZATION AND VALIDATION OF THE
DUTCH ADULT VERSION
W. De la Marche* (1), E. Scholte (2), J. Steyaert (1, 3), M.
Dorst (2), I. van Berckelaer-Onnes (2), I. Noens (4)
1. Child and Adolescent Psychiatry Dep., UPC-K.U.Leuven,
Belgium . Faculty of Social and Behavioral Sciences, Leiden
University, Netherlands 3. Clinical Genetics Dep., University
Maastricht, Netherlands 4. Faculty of Psychology and
Educational Studies, K.U.Leuven, Belgium
* wouter.delamarche@uz.kuleuven.be
Background: Autistic traits tend to be continuously distributed
in the general population. The Social Responsiveness Scale
(SRS) (Constantino et al., 2003) is a 65-item reporter based
questionnaire that has proven to quantify autistic traits in a
reliable way. We translated the adult research SRS into Dutch
and generated a self-report version of this questionnaire,
approved by Dr. Constantino and the original publisher.
Objectives: 1. To confirm the validity of the Dutch informant-
and self-report adult SRS in the general Dutch-speaking
population (the Netherlands and Flanders, Belgium). 2. To
describe the distribution of autistic traits as measured by the
SRS in the general population. Methods: Randomly selected
adults in the Netherlands and Flanders (Belgium) were asked
to fill out SRS questionnaires about themselves and their
partner and vice versa. Only questionnaires without missing
items were taken into account for the analyses. Results:
Preliminary results from the Netherlands (N=866 for
self-report, N=694 for partner-report) show a good test-retest
reliability (self-report: 0.90; partner-report: 0.91). Total
internal consistency is high for both versions of the Dutch
SRS (0.93 and 0.95), with two items not (or even negatively)
correlating with the total score. More results will be available
at the ISPG conference. Conclusions: Our results suggest that
the Dutch Social Responsiveness Scale for Adults and the
newly developed self-report version of this questionnaire have
psychometric properties comparable to the original SRS for
children, with a few small exceptions.
32 ASSOCIATION BETWEEN A HIGH-RISK AUTISM
LOCUS AND AUTISM-SPECTRUM
DISORDER-RELATED PHENOTYPES IN THE AVON
LONGITUDINAL STUDY OF PARENTS AND
CHILDREN (ALSPAC)
B. Glaser* (1), K. Wang (2), J. Glessner (2), J. Golding (3),
C. Steer (3), S. Grant (2), H. Hakonarson (2), G. Davey Smith
(1)
1. Medical Research Council Centre for Causal Analysis in
Translational Epidemiology and Department of Social
Medicine, University of Bristol, Bristol, UK 2. Children’s
Hospital of Philadelphia, Philadelphia, US 3. Centre for Child
and Adolescent Health, Department of Community Based
Medicine, University of Bristol, Bristol, UK
* B.Glaser@bris.ac.uk
Autism spectrum disorders (ASDs) are highly heritable
childhood neuro-developmental conditions, which are
characterised by impairment of social interaction and
communication, and repetitive interests, behaviours, and
activities. Recent genome-wide analysis revealed evidence for
a genetic variant on 5p14.1 (rs4307059), which is associated
with risk for ASD. It is unclear however if this risk variant
also relates to a quantitative trait locus underlying a broader
autism phenotype. We therefore studied association between
ASD-related phenotypes and variation in rs4307059 in up to
7313 ALSPAC children, representative of the general
population. For this we explored a battery of cognitive tests
and questionnaires, administered between the age of
15-months and 12-years, measuring early vocabulary and
communication patterns
(MacArthur-Communicative-Development-Inventory/MacArt
hur-Toddler-Communication-Questionnaire), intelligibility
(ALSPAC measure), social behaviour and behavioural
difficulties
(Emotionality-Activity-Sociability-Temperament-Survey;
Revised-Rutter-Parent-Scale for Preschool Children;
Standard-Assessment-Tests of social skills;
Strengths-and-Difficulties-Questionnaire, Cambridge
Hormones-and-Moods-Project-Friendship-Questionnaire;
Special-Educational Needs assessment), social communication
(Social-and-Communications-Disorders-Checklist;
Children’s-Communication-Checklist), verbal intelligence,real
world pragmatics and working memory
(Wechsler-Intelligence-Scale-for-Children-III). To overcome
the non-independent nature of our data and to account for
multiple testing and missing genotypes, we adopted a
permutation approach. Our study finds empirical evidence for
a joint association effect between ASD-related phenotypes and
rs4307059 (pEmp = 0.0015; SE = 0.0004), which is further
strengthened when the direction of each single effect is taken
into account (pEmp = 0.0004; SE = 0.0002). Our results show
that the observed profile of associations is unlikely to be the
result of chance suggesting that common variation in
rs4307059 is also associated with a broader ASD-phenotype.

33 SOCIAL RESPONSIVENESS: A QUANTITATIVE
INTERMEDIATE PHENOTYPE IN PARENTS OF
CHILDREN WITH AUTISM SPECTRUM DISORDERS.
W. De la Marche* (1)
1. Child and Adolescent Psychiatry Dep., UPC-K.U.Leuven,
Belgium
* wouter.delamarche@uz.kuleuven.be
Background: Although heritability of Autism Spectrum
Disorders (ASD) is up to 90%, finding specific genetic origins
has proven to be very difficult. A combination of several
genetic variants (Copy Number Variants, Single Nucleotide
Polymorphisms) with each a small effect on the ASD
susceptibility, inherited from both parents, might be the cause
of most of the ASD cases (Steyaert & De la Marche, 2008).
As a consequence, most parents of a child with ASD should be
carriers of some of those risk factors without having ASD
themselves. Carrying such a risk factor might result in
subclinical autistic traits. The Social Responsiveness Scale
(Constantino et al., 2003) has proven to reliably measure
autistic traits in a quantitative way in the general as well as in
the clinical population. Objectives: To assess if parents of a
child with ASD show autistic traits, intermediate between
control adults and adults with ASD. Methods: We asked
control adults, parents of children with ASD and adults with
ASD to fillout the Dutch self-report version of the Social
Responsiveness Scale and we asked their partners or parents to
fill out the other-report form. (Preliminary) Results: Total SRS
scores differ significantly between the three groups, both in
males and females (except for other-report in females,
possibly due to smaller sample), with parents of children with
ASD showing intermediate quantitative autistic traits.
Conclusions: These results support the hypothesis of multiple
genetic variants with a small effect each (additive polygenic
effect) inherited by the parents as a cause of ASD.
34 HLA AND AUTISM: CASE REPORT
M. Cojocaru* (1), C. Albu (1), D. Albu (1), E. Severin (1)
1. "Carol Davila" Univ Med Pharm
* genetics.dentistry@gmail.com
Background: Certain HLA alleles are known to be associated
with disease susceptibility. Few previous studies have shown
the association and linkage of HLA-A2 class 1 allele with
autism and other studies suggested that DR4 and DR13 alleles
are linked to autism spectrum disorder. Objective: our aim was
to evaluate HLA haplotype in a Caucasian family with a twin
pair discordant for autism. Subjects and Methods: A pair of
4-year-old twin male was evaluated and diagnosed by a
multidisciplinary team. Diagnostic criteria for autism were as
follows: impairment in social interaction, impairments in
communication and restricted repetitive and stereotyped
patterns of behavior, interests, and activities. The twin
zygosity was determined according to blood test: ABO blood
type system, Rh blood group system and HLA haplotype. The
parents had been typed for HLA haplotypes too. Results:
There was no family history of autism or autoimmune
disorders. The diagnosis of autism was early made because of
the language delay was present. Both twins showed language
impairment. One twin met criteria for autism and his co-twin
did not. Both twins had HLA A2 B18 DR13. The haplotype
was inherited from their mother. Conclusions: our results
suggest the role of HLA A2 and DR13 alleles as a genetic
susceptibility factor of autism.

35 THE OXYTOCIN RECEPTOR GENE (OXTR) IS
ASSOCIATED WITH AUTISM IN JAPANESE
POPULATION
X. Liu* (1), Y. Kawamura (2), T. Shimada (2), T. Otowa (2),
S. Koishi (2), Y. Kano (3), N. Kato (4), K. Tokunaga (5), T.
Sasaki (6)
1. Department of Human Genetics, Graduate School of
Medicine, University of Tokyo 2. Department of
Neuropsychiatry, Graduate School of Medicine, University of
Tokyo 3. Department of Child Psychiatry, The University of
Tokyo Hospital 4. Department of Psychiatry, School of
Medicine, Showa University 5. Department of Human
Genetics, Graduate School of Medicine, University of Tokyo
6. Health Service Center, University of Tokyo
* liuxiaoxi@m.u-tokyo.ac.jp
Purpose: Autism spectrum disorder (ASD) (OMIM: 209850)
is a neurodevelopment disorder characterized by impairment
in social interaction and communication as well as restricted
and stereotyped behaviors and interests. Previous research has
suggested the involvement of OXTR in the susceptibility to
ASD, and positive associations between OXTR and ASD were
observed in 4 independent studies from different ethnics
groups, In addition genome-wide linkage studies also have
indentified the chromosomal region Chr3 p25.3 as a candidate
region which harbors the OXTR gene, Despite these emerging
evidence, partial inconsistency of the previous findings
together with statistical issue regarding sample size and
statistical method still deserve further study In this study,we
attempted to replicate these recently published findings.
Method: we conducted 1) family based association test and 2)
population-based case-control test by using a total of 1210
Japanese samples, and 14 SNPs of OXTR gene were
genotyped. Result: Significant associations with ASD for both
single SNPs and haplotypes were observed in the present
study. We confirmed the previous associations of 1)
rs2254298 and rs53576 observed in Chinese population and of
the 2) 5’-flanking region of the exon 4 and a 3.5 kb region
within the third intron which were found in Caucasian
population. Conclusion: Our study demonstrates that SNPs
and haplotypes in the OXTR gene confer risk for ASD.
36 THE AUTISM GENOME PROJECT:
GENOME-WIDE ASSOCIATION STUDIES IN AUTISM
R. Anney* (1), o. the Autism Genome Project
1. Trinity College Dublin
* anneyr@tcd.ie
Autism spectrum disorders (ASD) are early onset
neurodevelopmental disorders affecting approximately 1/150
individuals and characterized by deficits in reciprocal social
interaction, communication and restricted and repetitive
patterns of behaviours and interests. Evidence to date supports
high heritability and a complex genetic aetiology. The Autism
Genome Project (AGP) is a large international collaboration
facilitating gene identification through access to a large
phenotypic and genetic dataset. We will present results from
genome-wide association (GWA) analyses from
approximately 3000 families genotyped using the Illumina 1M
BeadChip. To date results are available from over 1500 ASD
families. This resource is sufficiently large to implement
multiple analytical strategies for localizing CNVs and SNP
loci affecting risk for ASD. We are presenting data from
association analysis from the additive model across ancestral
groups (all, European) and partitions of the data split along
two diagnostic groups; any ASD (spectrum) and a narrow
diagnostic group (autism).Results to date implicate one gene
from the main analyses, namely MACROD2. While
significant for a single GWA, the p-value falls just below the
standard for GWA of approximately p=7.2x10-8. Other genes
previously described as associated to autism have also been
implicated by these analyses. The AGP is currently expanding
the dataset to complete a replication analysis. The analyses we
present will highlight both new loci and loci that continue to
show compelling evidence for association.

37 AUTISM SPECTRUM DISORDER AND PARENTAL
AGE IN JAPAN
T. Shimada* (1), Y. Kawamura (1), X. Liu (2), T. Otowa (1),
C. Kakiuchi (1), T. Umekage (3), H. Nishida (4), T. Sugiyama
(5), Y. Kano (6), K. Kasai (1), T. Sasaki (7)
1. Department of Neuropsychiatry, Graduate School of
Medicine, University of Tokyo 2. Department of Human
Genetics, Graduate School of Medicine, University of Tokyo
3. Division for Environment, Health and Safety, University of
Tokyo 4. Asunaro Hospital for Child and Adolescent
Psychiatry 5. Aichi Children’s Health and Medical Center 6.
Department of Child Psychiatry, University of Tokyo 7.
Office for Mental Health Support, University of Tokyo
* shimada-t@umin.net
Background: Genetic factor are strongly associated with
autism spectrum disorder (ASD), but other factors may also
play a significant role. Recent studies suggest that increased
maternal age and paternal age at birth are both associated with
an elevated risk of ASD. The biological mechanisms
underlying these relationships are not known. The association
maternal age with ASD may be because of the increased risk
of chromosomal abnormalities in ova of increased age or as a
result of unstable trinucleotide repeats. Paternal age may be
associated with ASD due to de novo spontaneous mutations
that accumulate with advancing age in spermatagonia, the
association may be confounded by sociocultural
environmental factors. We investigated parental age at birth of
children with ASD participating genetic study. Methods:
Maternal and paternal age at birth of 96 ASD children born in
1965-2002 were compared with those of children in the
Japanese general population using national statistics. Results:
The mean maternal age and paternal age at birth of ASD
children were 31.3 year and 34.4 year, respectively, which
were significantly higher than the expected parental age (29.0
year and 31.5 year, respectively) according to the national
statistics. Conclusions: Advanced parental age at birth might
be associated with the risk of ASD in the Japanese population.

EARLY CAREER INVESTIGATOR TRACK:
CANDIDATE GENES
ECI 7 USING DIMENSIONAL MODELS OF NICOTINE
DEPENDENCE TO AID IN GENE IDENTIFICATION ---
AN EXAMINATION OF THE NICOTINIC RECEPTOR
GENES
L. Chen* (1), R. Grucza (1), E. Johnson (2), N. Breslau (3),
D. Hatsukami (4), N. Saccone (5), T. Baker (6), S. Smith (6),
A. Goate (1), J. Rice (1), L. Bierut (1)
1. Department of Psychiatry, Washington University School of
Medicine, St. Louis, MO, USA 2. Research Triangle Institute
International3, Research Triangle Park, North Carolina 3.
Department of Epidemiology, Michigan State University, East
Lansing, Michigan 4. Department of Psychiatry, University of
Minnesota, Minneapolis, Minnesota, USA 5. Department of
Genetics, Washington University School of Medicine, St.
Louis, MO, USA 6. Department of Medicine, Center for
Tobacco Research and Intervention, University of Wisconsin
School of Medicine. Madison, WI
* chenli@psychiatry.wustl.edu
Introduction: Existing evidence suggests that nicotine
dependence is associated with genetic variants in nicotinic
receptor genes with phenotypic measures that strongly reflect
smoking heaviness such as cigarettes per day and FTND.
Nicotine dependence is multifactorial and it is unknown how
the nicotinic receptor genes relate to the range of dependence
factors. Methods: A community sample of 2073 European
American subjects participated in the COGEND study.
Phenotypic definitions including FTND, DSM, NDSS,
WISDM scores and subphenotypes including PDM, SDM,
daily cigarette use, and urgency to smoke in the morning were
assessed. Two hundred and twenty four SNPs in the α5-α3-β4
nicotinic receptor genes were analyzed. Results: The
multifactorial WISDM, and NDSS dependence measures
shared numerous significant associations with genetic variants,
while the DSM4 diagnostic phenotype shared few relations.
We found cigarette per day, NDSS drive subscale, WISDM
PDM subscales were highly associated with SNP rs16969968
and WISDM PDM subscale was highly associated with SNP
rs578776. We found the subphenotype craving showing the
strongest associations with both rs16969968 (involved in
amino acid changes in nicotinic receptor) and rs588765
(involved in mRNA expression in nicotinic receptor). We
demonstrated the differential associations between other
nicotinic receptors genes and dimensional phenotypes.
Conclusion: The phenotypic associations with rs16969968 are
strongest with a heavy smoking phenotype. Both SNPs
involved in biological mechanisms of nicotinic receptor
expression is validated by their convergent phenotypic
presentation in the craving subphenotype of WISDM. These
dimensional phenotypes and subphenotypes can be helpful in
refining the phenotypic characteristics associated with specific
gene clusters.
ECI 8 FUNCTIONAL POLYMORPHISMS IN THE
INTERLEUKIN 6 AND TUMOR NECROSIS FACTOR
GENES IN OBSESSIVE-COMPULSIVE DISORDER
C. Cappi (1), R. Muniz (1), A. Sampaio (1), S. Palácios (1), Q.
Cordeiro* (1), H. Brentani (1), A. Marques (2), H. Vallada
(1), E. Miguel (1), L. Guilherme (1), A. Hounie (1)
1. Sao Paulo University 2. National Institute of Health
* qcordeiro@yahoo.com
Obsessive-compulsive disorder (OCD) is characterized by
recurrent unwanted thoughts (obsessions), usually
accompanied by repetitive behaviors (compulsions) intended
to alleviate anxiety caused by obsessions. The role of the
immune system in central nervous system processes has long
been under investigation in the pathogenesis of a variety of
neuropsychiatric disorders. In this study, we investigated
polymorphisms of the genes that codify the cytokines TNF
and IL6 using a trio analysis approach, which minimizes
population stratification bias. Blood samples were obtained
from 71 OCD patients recruited at the University of São Paulo
Clinical Hospital and their 166 biological first-degree
relatives. All participants gave written informed consent. All
patients who had DSM-IV criteria for OCD and one or more
first-degree biological relatives (142 parents and 36 siblings)
willing to participate in the study were included. The analyses
were completed with PLINK software. The transmission
disequilibrium test was performed to measures the
over-transmission of an allele from heterozygous parents to
affected offspring. We found a significant association between
TNF rs1800795 polymorphism and OCD. The TNF rs1800629
was significantly associated only on the parental discordance
test. We haven’t found a significant association between IL6
rs13447446 polymorphism and OCD. This finding supports a
role for TNF in OCD. Plasma cytokine evaluation in OCD
patients as well as their polymorphisms may contribute to the
understanding of the role of immune factors in OCD etiology.

ECI 9 DRD1 PROMOTER REGION POLYMORPHISM
(RS4532) IS RECESSIVELY ASSOCIATED WITH
SCHIZOPHRENIA MARKED BY MILD SYMPTOMS
AND SPARED WORKING MEMORY
P. DeRosse* (1), T. Lencz (2), K. Burdick (2), A. Malhotra
(1)
1. Division of Psychiatry Research, The Zucker Hillside
Hospital 2. Center for Translational Psychiatry, The Feinstein
Institute for Medical Research
* pderosse@lij.edu
Background: A recent meta-analysis (Allen et al., Nat Gen, 40,
827-834) indicated that a promoter region variant (rs4532,
-48A/G) in the DRD1gene was one of only four SNPs with
strong evidence for association to schizophrenia (SZ). Even
so, the effect size was modest (allelic OR=1.18,
95%CI=1.01-1.38), with relatively modest sample size (725
cases). Additionally, mode of transmission was not clarified,
and effects on clinical phenotypes such as symptom scores and
cognitive performance has not been reported. Methods:
Caucasian SZ cases (n=280) and controls (n=250) were
genotyped using the Affymetrix 500K array, and rs4532
genotype was imputed with high confidence (>0.87) using
HapMap/Mach. Symptom scores were assessed using the
SCID-IV, based on lifetime presence indicated by self-report,
and, in most cases, verified by informant report and/or
extensive chart records. A brief neurocognitive battery was
administered containing 6 primary measures. It was
hypothesized that digit span performance would be
specifically affected by DRD1 genetic variation based on
long-standing evidence of a relationship between prefrontal
D1 receptor function and working memory performance.
Results: Patients with schizophrenia were significantly
(p=0.005; OR=1.44; 95%CI=1.11-1.86) more likely to carry
the minor (G) allele, strengthening the prior meta-analytic
results and increasing the patient sample by nearly 40%.
Additionally, results were most consistent with a recessive
model of transmission (OR=2.2; 95%CI=1.25-3.90). While
GG homozygotes were thus more than twice as likely to be
classified as cases, these patients were marked by reduced
severity across multiple symptom domains (auditory
hallucinations, alogia, and disorganized behavior). Moreover,
patients carrying the GG genotype demonstrated relatively
spared working memory (approximately 1 point difference on
digits backward, p=.003). Conclusions: A SNP in the
promoter region of DRD1 is reliably associated with
schizophrenia, possibly in a recessive mode of transmission.
Interestingly, this SNP appears to be associated with a
relatively mild clinical and cognitive presentation.
ECI 10 CHILDHOOD MALTREATMENT AND MAOA
GENOTYPE: AN INVESTIGATION OF MAIN AND
INTERACTIVE EFFECTS ON DIVERSE CLINICAL
EXTERNALIZING OUTCOMES
J. Derringer* (1), R. Krueger (1), D. Irons (2), W. Iacono (2)
1. Department of Psychology, Washington University in St.
Louis 2. Department of Psychology, University of Minnesota
* derringer@wustl.edu
We studied the impact of MAOA genotype and retrospectively
reported childhood maltreatment (physical and/or sexual) on
young adult lifetime clinical externalizing symptoms
(substance problems, adult antisocial behavior, and conduct
disorder). Participants were 841 individual twins from the
community-based Minnesota Twin Family Study assessed
through age 25. Childhood maltreatment was associated with
increasing symptoms for substance problems, antisocial
behavior, and conduct disorder. No significant main effects of
MAOA were observed on any phenotype, nor were there
significant GxE interactions between MAOA and harsh
discipline on any phenotype or a significant interaction
between MAOA and childhood sexual assault on substance
problems. We did, however, find evidence that childhood
sexual assault interacted with MAOA genotype to predict
antisocial behavior (p=0.014, R2=0.4%) and conduct disorder
symptoms (p=0.007, R2=0.7%). Individuals with the low
MAOA activity genotype who reported childhood sexual
assault had more symptoms than individuals with either the
high MAOA activity genotype and/or no history of childhood
sexual assault. These findings suggest that the previously
reported interaction between MAOA and childhood
maltreatment is specific to the aggressive subset of
externalizing disorders.

ECI 11 ASSOCIATION BETWEEN SIGMA1
RECEPTOR GENE A61C (GLN2PRO) AND
SEROTONIN RECEPTOR 1A PROMOTER -1019C>G
POLYMORPHISM AND PANIC DISORDER IN
JAPANESE POPULATION.
Y. Konishi* (1), H. Tanii (1), T. Otowa (2), T. Sasaki (3), H.
Kaiya (4), Y. Okazaki (5)
1. Department of Psychiatry, Mie University 2. Department of
Psychiatry, University of Tokyo 3. Health Service Center,
University of Tokyo 4. Warakukai Panic Disorder Clinical
Research Center 5. Metropolitan Matsuzawa Hospital
* konikonikoni1029@hotmail.co.jp
Panic disorder (PD) is a disease characterized by an uneasy
feeling accompanied by two or more physical symptoms
caused by abnormality of the autonomic nerve system, such as
palpitation, perspiration, chest unpleasantness, a feeling of
dizziness, and the like. These symptoms are not necessarily
repeated with each attack of PD. PD is considered to have
significant genetic factors in the etiology. Sigma1 receptor
(Sig-1R) is considered to modulate the function
N-methyl-D-aspartate (NMDA) receptors and have strong
affinity with fluvoxamine, a typical therapeutic drungs of PD.
Serotonin receptor 1A (5-HT1A) gene is proposed to be one of
pathogenic factors for panic disorder related with serotonin
system. Regarding 5-HT1A receptor promoter -1019C>G
polymorphism, it was shown that the G allele significantly
correlated with panic disorder with agoraphobia. A study of
PD patients using fMRI showed that for patients homozygous
for G allele, fearful stimuli were associated with a decreased
activation of the right prefrontal cortex. In these context, we
studied in this study single-nucleotide polymorphisms (SNPs)
of Sig-1R A61C (Gln2Pro) and 5-HT1A receptor promoter
-1019C>G polymorphism in Japanese patients with PD and
controls. No significant association was observed between the
two SNPs and PD. We therefore conclude that the Sig-1R
A61C (2Gln2Pro) and 5-HT1A receptor -1019C>G
polymorphism may not play a major role in PD in Japanese
populations.
ECI 12 AMYLOID PRECURSOR PROTEIN-BINDING
PROTEIN A2 (APBA2) IS AN AUTISM CANDIDATE
GENE
T. Babatz (1), R. Kumar* (1), J. Sudi (1), W. Dobyns (1), S.
Christian (1)
1. The University of Chicago
* rkumar1@bsd.uchicago.edu
Background: We have previously reported an autistic proband
and affected brother harboring a maternally inherited 289 kb
microduplication of 15q13.1, a region previously associated
with autism, schizophrenia and mental retardation. APBA2 is
located within 15q13.1 and encodes a synaptic protein that
interacts directly with the autism-associated protein NRXN1.
Mice deleted for APBA2 show abnormal social behaviors. We
hypothesize that rare genetic variation of APBA2 underlies
risk for autism. Objectives: To screen APBA2 for rare
nucleotide variation in autistic individuals and controls.
Methods: Sanger sequencing was used to screen the coding
regions of APBA2 in 512 autism samples and 463 control
individuals. Bioinformatics approaches were used to evaluate
the functional effects of APBA2 variants. Results: We
identified seven novel autism-specific non-synonymous
coding variants, all of which are predicted to affect protein
function and/or alter residues that are conserved across all 28
species examined. We identified four non-synonymous
variants specific to controls, indicating no significant
difference in mutation burden between cases and controls. Of
particular interest were two non-synonymous coding variants
that were identified in two sibs with autism: (1) a
paternally-inherited heterozygous 6-bp deletion and (2) a
maternally-inherited heterozygous missense mutation. These
results suggest compound heterozygous mutations of APBA2
in this autism sibship. Conclusions: This work represents the
first sequence-level evaluation of APBA2 as an autism
candidate. The co-occurrence of two non-synonymous
mutations in both affected siblings in a single family, each
transmitted from a different unaffected parent, may indicate a
causative role for APBA2 mutations in this isolated case.

CANDIDATE GENES
38 GWAS PROGRAM OF CHINA AND ITS
APPLICATION IN THE STUDY OF PSYCHIATRIC
DISEASES
L. He* (1), Y. Shi (1), G. He (1), G. Feng (1)
1. Bio-X Center, Shanghai Jiao Tong University
* helinhelin@gmail.com
GWAS, a powerful measure although it can be not perfect
from some recent overviews, has geared up association studies
of causative genes to common complex diseases, including
psychiatric diseases that have caused severe problems for
societies, in the West particularly. As a slow coach, however,
China finally decided to initiate its own nationwide GWAS
program. It can be pretty late but fortunately as the etiologies
of those diseases are versatile and the genetic backgrounds
vary in different populations, it is very necessary to study the
genetic factors in each population individually. In recent
years, Chinese researchers have started to generate some data
based on GWAS including genome-wide association, cnv,
epigenomics, and microRNA-based work to dig out genetic
etiology of some psychiatric diseases with the Chinese
samples. In my presentation, I will show recent advances with
several GWAS-based studies of psychiatric diseases.
39 MAJOR DEPRESSION, ANXIETY AND THE
NOREPINEPHRINE TRANSPORTER
H. Buttenschøn* (1), H. Buch (1), A. Kristensen (1), J.
Thomsen (2), S. Mikkelsen (2), J. Bonde (3), H. Kolstad (4),
L. Kærlev (4), A. Kærgaard (4), J. Andersen (4), A. Hansen
(5), R. Rugulies (5), A. Børglum (6), O. Mors (1)
1. Centre for Psychiatric Research, Aarhus niversitetshospital,
Risskov, Denmark 2. Department of Occupational Medicine,
Glostrup University Hospital, Denmark 3. Bispebjerg
University Hospital, Denmark 4. Danish Ramazzini Centre,
Department of Occupational Medicine, Aarhus University
Hospital, Denmark 5. National Research Centre for the Work
Environment, Copenhagen, Denmark 6. Inst. of Human
Genetics, Aarhus University, Denmark
* henrbutt@rm.dk
Background: Genetic factors play important roles in the
etiology of anxiety and depressive disorders. Symptoms of
anxiety and depression commonly co-occur, and high rates of
comorbidity among anxiety and depressive disorders are
well-established. The aim of the present study was to explore
321 tagSNPs in 20 candidate genes for association with
anxiety and/or depression, respectively. The genes were
selected based on their function in norepinephrine signalling,
serotonin signalling, the hypothalamic-pituitary-adrenal
(HPA) axis or their involvement in neuroplasticity. Method:
The case-control sample consisted of 331 patients with major
depression, 219 patients with anxiety disorders and 297
ethnically matched controls. Cases and controls were
interviewed with the semi-structured diagnostic interview
Schedules for Clinical Assessment in Neuropsychiatry
(version 2.1). The genotyping were performed using the
Sequenom platform (Sequenom, Inc, San Diego, USA). To
test for allelic, genotypic, and haplotypic association the
PLINK software was used
(http://pngu.mgh.harvard.edu/purcell/plink/). Results: A
number of genes showed significant association with
depression and anxiety. However, the norepinephrine
transporter (NET) appeared to be the most significantly
associated gene in the anxiety sample. Five SNPs within the
gene appeared to be allelic, genotypic and haplotypic
associated with anxiety. The NET gene also appeared to be
significantly associated with depression. In total six SNPs,
five of which also were associated with anxiety, were allelic,
genotypic and haplotypic associated with depression.
Discussion: The present study suggested the NET gene as a
common susceptibility gene for depression and anxiety.

40 CNV OVERLAPPING GSK3beta (GLYCOGEN
SYNTHASE KINASE-3beta) GENE AND ITS
ASSOCIATION WITH MOOD DISORDERS
PHENTOYPES IN SPANISH POPULATION
E. Saus* (1), V. Soria (2), G. Escaramís (3, 5), J. Crespo (2,
5), J. Valero (6), A. Guitiérrez-Zotes (6), L. Martorell (6), E.
Vilella (6), J. Menchón (2, 5), X. Estivill (1, 3), M.
Urretavizcaya (2, 5), M. Gratacòs (1, 3)
1. Genetic Causes of Disease Group, Genes and Disease
Program, Center for Genomic Regulation (CRG-UPF),
Barcelona, Catalonia, Spain. 2. CIBERSAM (CIBER en Salud
Mental), Mood Disorders Clinical and Research Unit,
Psychiatry Department, Bellvitge University Hospital,
Barcelona, Spain. 3. CIBER en Epidemiología y Salud Pública
(CIBERESP), Instituto de Salud Carlos III, Madrid, Spain 4.
Genetic Causes of Disease Group, Genes and Disease
Program, Center for Genomic Regulation (CRG-UPF),
Barcelona, Catalonia, Spain. 5. Department of Clinical
Sciences, Bellvitge Campus, Barcelona University, Barcelona,
Spain. 6. Grup d’Investigació en Psiquiatria. Hospital
Universitari Institut Pere Mata, Rovira i Virgili University,
Reus, Spain.
* ester.saus@crg.es
Glycogen synthase kinase-3β (GSK3β) is known to regulate
critical cellular functions and recent findings support that may
play a role in the pathophysiology and treatment of mood
disorders (MD). Lachman et al. (2006) found an increased
number of gains in a CNV (copy number variant) partially
overlapping with GSK3β in bipolar patients compared with
control individuals. Here, we replicated this experiment in a
Spanish sample of MD under the hypothesis that this CNV
could partially underlie the susceptibility to MD and also
could be associated with specific clinical subphenotypes. The
sample consisted of 444 MD patients (256 Unipolar
Depressive Disorder, 188 Bipolar Disorder) and 428
psychiatrically screened controls. All samples were genotyped
in triplicate by qPCR. Triplicates undergone a quality control
measure, and a linear mixed model was generated to
normalize all the data allowing a posterior relative
quantification of gains and losses. We found a total of 42
samples with gains and 13 samples with losses (18 gains and 4
losses in MD patients, and 24 gains and 9 losses in controls).
An association study considering MD vs. controls adjusting by
age and sex was performed, but no significant result was
obtained. Then, we tested 5 clinical subphenotypes in MD:
polarity, seasonality, chronotype, antidepressant treatment
response and age at onset. Only seasonality scores were
nominally associated. While we have not been able to confirm
a direct involvement of GSK3β CNV in the susceptibility to
MD, changes in copy number in GSK3β could partially
contribute to seasonal pattern in MD.
41 ASSOCIATION BETWEEN POLYMORPHISMS IN
THE METALLOPHOSPHOESTERASE (MPPE1) GENE
AND BIPOLAR DISORDER
F. Lohoff* (1), T. Ferraro (1), E. Brodkin (1), A. Weller (1),
P. Bloch (1)
1. University of Pennsylvania
* lohoff@mail.med.upenn.edu
Genetic linkage studies in bipolar disorder (BPD) suggest that
a susceptibility locus exists on chromosome 18p11. The
metallophosphoesterase (MPPE1) gene maps to this region.
Dysregulation of protein phosphorylation and subsequent
abnormal cellular signaling has been postulated to be involved
in neuropsychiatric disorders thus making MPPE1 a plausible
biological candidate gene for BPD. In this study, we
hypothesized that genetic variation in the MPPE1 gene
contributes to BPD. We tested this hypothesis by genotyping 4
SNPs (rs871044; rs3974590; rs593713; rs602201) in BPD
patients (n=570) and healthy controls (n=725). Genotypes and
allele frequencies were compared between groups using Chi
square contingency analysis. Linkage disequilibrium (LD)
between markers was calculated and estimated haplotype
frequencies were compared between groups. Single marker
analysis revealed an association of rs3974590 with BPD
(p=0.009; permutation corrected p=0.046). Haplotype analysis
did not show any significant association with disease after
permutation correction. Our results provide evidence of an
association between a polymorphism in the MPPE1 gene and
BPD. Additional studies are necessary to confirm and
elucidate the role of MPPE1 as a susceptibility gene for BPD
on chromosome 18p.

42 A MULTI-DEMENSIONAL EVIDENCE-BASED
CANDIDATE GENE PRIORITIZATION APPROACH
FOR SCHIZOPHRENIA AND OTHER COMPLEX
DISEASES
J. Sun (1), P. Jia (1), A. Fanous (2), B. Webb (3), E. van den
Oord (3), B. Riley (3), X. Chen (3), J. Bukszar (3), K. Kendler
(3), Z. Zhao* (1)
1. Vanderbilt University 2. Washington VA Medical Center 3.
Virginia Commonwealth University
* zhongming.zhao@vanderbilt.edu
Introduction: During the past decade we have seen an
exponential growth of vast amounts of genetic data generated
for complex disease studies. Across a variety of complex
biological problems currently, there is a strong trend towards
the integration of data from multiple sources. So far, candidate
gene prioritization approaches have been designed for specific
purposes, by utilizing only some of the available sources of
genetic studies, or by using a simple weight scheme.
Specifically to psychiatric disorders, there has been no
prioritization approach that fully utilizes all major sources of
experimental data. Methods: Here we present a
multi-dimensional evidence-based candidate gene
prioritization approach for schizophrenia. In this approach, we
first collect and curate genetic studies for schizophrenia from
four major categories: association studies, linkage analyses,
gene expression, and literature search. Genes in these data sets
are initially scored by category-specific scoring methods.
Then, an optimal weight matrix is searched by a two-step
procedure (core genes and unbiased P values in independent
genome-wide association studies). Finally, genes are
prioritized by their combined scores using the optimal weight
matrix. Results: The prioritized genes were evaluated by the
enriched P values in two independent GWA studies and also
by gene expression pattern in human tissues. The evaluation
suggests this approach generates prioritized candidate genes
that are promising for further analysis or replication. For
example, our follow up gene network/pathway analysis using
these prioritized candidate genes suggested a few novel
candidate genes, one of which was successfully verified in our
Irish Case-Control Study of Schizophrenia (ICCSS)
sample. Conclusions: The approach can be applied to other
complex diseases, especially other psychiatric disorders.
43 MATERNAL MTHFR C677T GENOTYPE &
DEPRESSED MOOD DURING PREGNANCY AFFECTS
SLC6A4 METHYLATION IN INFANTS AT BIRTH
R. Wade (1), T. Oberlander (1), U. Brain (1), J. Austin* (1),
A. Devlin (1)
1. UBC
* jehannine.austin@ubc.ca
In utero and early postnatal exposure to depressed maternal
mood may program childhood behaviour via epigenetic
processes. Methylenetetrahydrofolate reductase (MTHFR) is
an enzyme important for methyl metabolism. A common
variant in the MTHFR gene, C677T, is associated with
depression. We investigated the effect of maternal MTHFR
C677T genotype on maternal mood (Edinburgh Postnatal
Depression Scale, EPDS), during pregnancy (n=82 women, all
receiving folate supplements) and on promoter methylation of
two genes implicated in depression, brain derived
neurotrophic factor, BDNF, and sodium-dependent serotonin
transporter, SLC6A4, in the women and their infants at birth.
Women with the MTHFR 677TT genotype had greater
(P

44 HTR1B AS A RISK PROFILE MAKER IN
PSYCHIATRIC DISORDERS: A REVIEW THROUGH
MOTIVATION AND MEMORY
A. Drago* (1), D. De Ronchi (1), A. Serretti (1)
1. University of Bologna
* antonio.drago@unibo.it
HTR1B receptor is involved in the regulation of the serotonin
system, playing different roles in specific areas of the brain.
Consistently, HTR1B manipulation in animals results into
altered behavior possibly related to psychiatric disorders. We
here review HTR1B, its product and its functional role in the
neuronal nets involved in motivation and memory. Then, we
go the other way round and analyze how and how much
HTR1B variations impact the psychiatric phenotypes mainly
associated with these functions. The neuronal nets involved in
motivational and mnemonic functions are described, and the
role played by HTR1B in these systems is depicted: as a
result, a picture of the relevance of HTR1B in the modulation
of motivation and memory is attained. By contrast, the review
of the genetic association studies resulted into partial evidence
sustaining HTR1B relevance toward substance related and
obsessive compulsive disorders and no solid evidence toward
other psychiatric disorders.
45 POLYMORPHIC VARIANTS AND DIFFERENTIAL
EXPRESSION OF DPYSL2 IN SCHIZOPHRENIA
C. Winchester* (1), M. Bailey (2), P. Johnson (2), L.
O'Donovan (2), B. Morris (2), J. Pratt (1)
1. University of Strathclyde 2. University of Glasgow
* c.winchester@bio.gla.ac.uk
We identified DPYSL2 as a candidate gene for schizophrenia
from a microarray analysis of the prefrontal cortex of a rodent
phencyclidine (PCP) model of schizophrenia, developed in our
laboratory 1,2. This PCP model produces a pattern of
metabolic hypofunction, neurochemical changes and
behavioural deficits in the prefrontal cortex that closely mirror
the cognitive deficits of schizophrenia 1,2. Location of the
gene within a linkage and association peak in chr. 8p21, its
function in neuronal development and its interactions with
proteins otherwise implicated in the pathophysiology of
schizophrenia (e.g. SEMA3A, DISC1, GSK3, CTNNB1) also
support DPYSL2 as a plausible candidate gene for
schizophrenia. We performed a case-control association study
of DPYSL2 in DNA samples from 500 UK patients with
DSM-IV schizophrenia and 500 ethnically similar normal
controls. ABI TaqMan assays were used to genotype 11 tag
SNPs across several haplotype blocks. Association of
schizophrenia with individual SNPs was tested using a variety
of Chi squared tests and the Armitage Trend test. Haplotypes
have been predicted and analysis is underway. Five SNPs
encompassing a region in the 3’ half of DPYSL2, previously
implicated in schizophrenia, showed modest associations with
schizophrenia in our sample (best P = 0.021 for rs13277175
under a G allele-dominant model; O.R. = 1.35 [1.045-1.752,
95% C.I.]). DPYSL2 transcripts have been analysed by
quantitative RT-PCR in schizophrenia patient and control
post-mortem dorsolateral prefrontal cortex and showed that
transcript levels are associated with genotype at several of the
associated SNPs. We present converging evidence for
DPYSL2 as a risk factor for schizophrenia. 1. Cochran et
al.2003. Neuropsychopharmacology. 28 (2):265-275 2. Pratt et
al. 2008. British Journal of Pharmacology 153, S465-470 This
work was funded by NHS Scotland R&D for Mental Health
Research.

46 LACK OF SUPPORT FOR THE ASSOCIATION OF
PER3, CSNK1E, AND CLOCK GENE WITH
MORNINGNESS-EVENINGNESS IN YOUNG ADULT
FEMALE
E. Joo* (1), K. Lee (1), H. Kim (1), K. Choi (1)
1. Eulji University
* jej1303@gmail.com
Circadian rhythm is known to be genetic. Multiple SNPs in
clock genes have been searched for a possible association with
circadian rhythm. The association was tested in normal
population as well as psychiatric patients group such as
bipolar disorder. Recent genetic studies reported that in
unrelated bipolar patients some clock genes were associated
with morningness-eveningness measurement scale. We
explored possible association of several promising SNP
showed positive association in previous studies with
chronotype in a young adult female group. We collected
phenotype data and blood from 804 young Korean adult
females. Most of them were nurses working on shift schedule.
Morningness-eveningness was measured with 13 items
Composite Scale. DNA was extracted from the blood and
genotyping was done in TaqMan assay method. We selected 4
polymorphic sites from three different clock genes: 1 SNP and
1 VNTR from PER3 gene, 1 SNP from CSNK1E gene, and 1
SNP from CLOCK gene. Associations were analyzed based on
individual and epistatic interaction of polymorphic sites. We
could not find any association of PER3, CSNK1E, and
CLOCK gene with Composite Scale scores in individual
genotype as well as analysis for epistatic interaction between
polymorphic sites. Morningness-eveningness seems complex
as a trait. Clock genes could not support clock genes as a
significant contributor for chronotypes, however the size of
SNPs to be tested were small in this study. More studies with
bigger sample size including males would be required.
47 ASSOCIATION STUDY OF CHRNA7 WITH
SCHIZOPHRENIA AND BIPOLAR DISORDER IN
KOREAN POPULATION
E. Joo* (1), K. Lee (1), S. Kim (2), Y. Ahn (2), Y. Kim (2)
1. Eulji University 2. Seoul University
* jej1303@gmail.com
CHRNA7 has been known a strong candidate gene for
schizophrenia. It is located on chromosome 15q13-q14, one of
the replicated linkage spot of schizophrenia. We conducted an
association study to replicate previous positive findings in
Korean population. We included 254 patients with
schizophrenia, 193 patients with bipolar disorder type I, 38
patients with bipolar disorder type II, 64 schizoaffective
disorder patients, and 349 controls. Total 898 subjects were
included and genotyping were done for three SNPs of
CHRNA7. Those 3 SNPs are rs2337506 (A/G, intron),
rs6494223 (C/T, intron), and rs12916879 (A/G, intron).We
found a marginally significant association with rs12916879
with bipolar disorder type I. Both allele and genotype-wise,
we found a weak signal (chisquare=3.568, df=1, p=0.059 for
allele, chisquare=7.504, df=2, p=0.023 for genotype). Sliding
window haplotype analysis using UNPHASED could not find
any significant association. Other polymorphism was not
associated with schizophrenia or bipolar spectrum disorders in
this population. Further analysis with more SNPs is required
to reveal the role of CHRNA7 in schizophrenia and bipolar
spectrum disorders.

48 ALLELIC EXPRESSION IMBALANCE ANALYSIS
OF ANK3 AND CACNA1C PROVIDES STRONG
EVIDENCE OF CIS-ACTING VARIATION
AFFECTING EXPRESSION OF BOTH GENES.
E. Quinn* (1), M. Hill (1), R. Anney (1), M. Gill (1), A.
Corvin (1), D. Morris (1)
1. Neuropsychiatric Genetics Research Group, Department of
Psychiatry and Institute of Molecular Medicine, Trinity
College Dublin, Ireland.
* quinne5@tcd.ie
Genome-wide association studies (GWAS) have identified
ANK3 and CACNA1C as susceptibility genes for bipolar
disorder. Available biological information on these genes
suggests a potential molecular mechanism involving ion
channel dysfunction. The associated SNPs at ANK3
(rs10994336) and CACNA1C (rs1006737) are both intronic
with no obvious impact on gene function. Instead of affecting
the protein function, these risk variants may impact on gene
regulation affecting expression. Testing for allelic expression
imbalance (AEI) is a method of identifying such cis-acting
regulatory polymorphisms by using a coding DNA marker
SNP to assay relative allelic abundance in cDNA compared to
genomic DNA. The primary aim of this study was to examine
ANK3 and CACNA1C for regulatory polymorphisms
contributing to differential gene expression in HapMap CEU
lymphoblastoid cell lines. If detected, the secondary aim was
to determine if the strong GWAS signals reported for these
genes could be attributed to these functional SNPs. AEI was
successfully detected at ANK3 and CACNA1C using coding
marker SNPs rs3750800 and rs1544514 respectively,
indicating the presence of cis-acting variants at both loci.
There was considerable evidence of AEI at ANK3 with more
than half of all heterozygous samples (21 out of 34) showing
AEI and a small number of samples showing near
mono-allelic expression. However, the AEI at either gene
could not be attributed to the GWAS-associated SNPs. These
data indicate that there is genetic variation local to both genes
that is affecting their expression, but this variation is not
responsible for increasing risk of bipolar disorder.
49 RELEVANT FINDINGS ON THE GENES OF
SEROTONERGIC SYSTEM AND SUICIDE IN
SLOVENIA
A. Videtic* (1), T. Zupanc (2), J. Balazic (2), P. Pregelj (3),
R. Komel (1)
1. Institute of Biochemistry, Faculty of Medicine, University
of Ljubljana, Vrazov trg 2, Ljubljana, SI-1000, Slovenia 2.
Institute of Forensic Medicine, Faculty of Medicine,
University of Ljubljana, Korytkova ulica 2, Ljubljana,
SI-1000, Slovenia 3. University Psychiatric Clinic Ljubljana,
Studenec 48, Ljubljana Polje, SI-1260, Slovenia
* alja.videtic@mf.uni-lj.si
In Europe, countries with the highest suicide rates form a
so-called J-curve, which starts in Finland and extends south to
Slovenia – a country with one of the world’s highest suicide
rates. In 2006 there were 529 suicides, with the rate of 26.3
suicide victims per 100.000 citizens, most of the victims being
between 35 and 64 years years of age. Suicide is a complex
phenomenon, influenced by environmental and genetic
factors, where for the latter the most interesting results were
obtained for serotonergic system. In our study we performed
molecular-genetic analysis on polymorphisms 68G>C and
-995G>A in serotonin 2C receptor gene, and -1019 C>G in
serotonin 1A receptor gene, on 334 suicide victims and 312
controls. For 62 suicide victims psychological autopsy was
available. A significantly different distributions for
polymorphism 68G>C were observed in two cases: between
genotypes of female suicide victims and controls
(P(FET)=0.008) and in alleles of female and male populations
(P=0.005). An excess of GG genotype and allele G was
observed. Haplotype analysis showed marginal association of
haplotype G-C (-995G, 68C) with suicide only in female
population. For polymorphism -1019C>G data on stressful life
events of suicide victims was available. More stressful life
events in the month prior to the suicide were reported for the
subgroup with CC genotype (mean number of events=2.53;
SD=1.50) in comparison to subgroup with CG/GG genotypes
(mean number of events=1.58; SD=1.32; P

50 ASSOCIATION OF THE GABRD GENE AND
CHILDHOOD-ONSET MOOD DISORDERS
Y. Feng* (1), K. Kapornai (2), E. Kiss (2), Z. Tamás (3), L.
Mayer (2), I. Baji (3), G. Daróczi (2), I. Benák (2), V.
Kothencné (2), E. Dombovári (2), E. Kaczvinszk (2), M.
Besnyo (3), J. Gádoros (3), J. Székely (4), M. Kovacs (5), Á.
Vetró (2), J. Kennedy (6), C. Barr (1, 7)
1. Toronto Western Hospital 2. Szeged University 3.
Vadaskert Hospital 4. Semmelweis University 5. University of
Pittsburgh School of Medicine 6. Centre for Addiction and
Mental Health 7. The Hospital for Sick Children
* yfeng@uhnres.utoronto.ca
The chromosome 1p36 region was previous indicated as a
locus for susceptibility to recurrent major depressive disorder
based on a linkage study in a sample of 497 sib pairs. We
investigated the GABAA d receptor subunit gene, GABRD, as
a susceptibility gene to childhood-onset mood disorders
(COMD) because of substantial evidence implicating
GABAergic dysfunction in mood disorders and the position of
this gene in the 1p36 linkage region. Using a sample
consisting of 603 Hungarian families with a child/adolescent
proband diagnosed with a mood disorder with the onset of the
first episode before age 15, we found evidence for association
of two polymorphisms located within the gene, rs2376805 and
rs2376803, as well as haplotypes of these two markers.
Further, significant evidence of association was only observed
in male subjects when the results were analyzed by sex. This
was in contrast with the previous linkage findings, as LOD
scores exceeding 3 were only in female-female pairs in that
study. These findings point to the GABRD gene as a
susceptibility gene for COMD, however, this gene may not
explain the previous linkage finding.
51 GPR50, A CANDIDATE FOR BIPOLAR DISORDER,
AFFECTS NEURITE OUTGROWTH
E. Gruenewald (1), H. Kinnell (2), D. Porteous (1), P.
Thomson* (1)
1. Medical Genetics Section, MMC. The University of
Edinburgh.UK 2. MRC Human Reproductive Science Unit,
Edinburgh, UK
* pippa.thomson@ed.ac.uk
In the search for candidate genes for major mental disorders,
X-linked orphan G protein-coupled receptor 50 (GPR50), also
termed melatonin-related receptor, was identified as a risk
gene for bipolar disorder. G protein-coupled receptors are
important susceptibility candidates for disease as they are
involved in molecular signaling pathways and are major
targets of drug treatment. The function of GPR50 is unclear
and no ligand has yet been identified. In order to understand
its function, a yeast two-hybrid study was performed,
identifying putative interactors with the C-terminal region of
GPR50. Key interactors are known to be involved in neuronal
development and lipid metabolism. In this study we report a
follow up of one biologically interesting interactor: a potent
neurite outgrowth inhibitor, which has also been implicated in
apoptosis, schizophrenia, bipolar disorder and Alzheimer’s
disease. We confirmed the interaction, by
immunocytochemistry and co-immunoprecipitation.
Furthermore, we performed expression analysis of both genes
in the developing mouse brain. Interestingly, we have
identified a possible functional interaction between GPR50
and this protein. Transient GPR50 over-expression results in
extended neurites (p

52 ASSOCIATION STUDY OF GENES INVOLVED IN
A-TO-I RNA EDITING IN BIPOLAR DISORDER AND
SCHIZOPHRENIA PATIENTS FROM AN ISOLATED
NORTHERN SWEDISH POPULATION.
S. Ceulemans* (1), M. Alaerts (1), D. Forero (1), S. De Zutter
(1), K. Norrback (2), L. Moens (1), R. Adolfsson (2), J.
Del-Favero (1)
1. Applied Molecular Genomics Group, VIB Department of
Molecular Genetics, Belgium University of Antwerp (UA),
Antwerpen, Belgium 2. Department of Clinical Sciences,
Division of Psychiatry, Umeå University, Sweden
* shana.ceulemans@molgen.vib-ua.be
Bipolar (BP) disorder and schizophrenia (SZ) are among the
most commonbrain diseases worldwide with a large impact on
both the patients and theirrelatives’ lives. The observation that
receptor subunits of twoimportant neurotransmitters of the
central nervous system, glutamate andserotonin, undergo
A-to-I RNA editing by “Adenosine Deaminases Acting on
RNA” (ADARs) supports the hypothesis that this modification
is potentially involvedin the etiology of psychiatric disorders.
In our search for BP disorder and SZ susceptibility genes, we
are exploring the malfunctioning and/or deficiency of the
A-to-I RNA editingprocess. Hereto, a HapMapbased
association study of the genes ADAR, ADARB1 and GRIA2
was performed by genotyping a total of 90 (h)tSNPs inBP
patients (N=316); SZ patients (N=486) and matched control
individual (n=512) originating from a northern Swedish
isolated population. Single marker and haplotype specific
statistical analyses showed significant association of several
ADARB1 SNPs withBP as well as with LD-blocks of
ADARB1with BP disorder. In addition, ADARB1gave also
rise to an associated haplotype with SZ. Together, these
resultsindicate that ADARB1 should befurther explored to
unravel its genetic contribution to the etiology of BP disorder
and SZ. Furthermore,single marker association was found for
ADARwith SZ (P=0,027) and for GRIA2 withBP disorder
(P=0,006).Taken together, the results of this association study
show that A-to-I RNA editing ispotentially involved in the
susceptibility to psychiatric disorders.
53 ASSOCIATION OF NEUROTROPHIN RECEPTOR
(NTRK-3) GENE POLYMORPHISMS WITH BIPOLAR
DISORDERS
S. Djurovic* (1, 2, 3), M. Mattingsdal (1), L. Athanasiu (2, 3),
I. Melles (1, 3), I. Agartz (1, 4), S. Lorentzen (1, 5), G.
Morken (6), O. Andreassen (1, 3)
1. Institute of Psychiatry, University of Oslo, Oslo, Norway 2.
Department of Medical Genetics; Oslo University Hospital -
Ulleval, Oslo, Norway 3. Department of Psychiatry; Oslo
University Hospital - Ulleval, Oslo, Norway 4. Department of
Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
5. Department of Psychiatry, Oslo University Hospital –Aker,
Oslo, Norway 6. Østmarka Psychiatric Department, St Olavs
Hospital and Institute of Neuroscience, Norwegian University
of Technology and Science, Trondheim, Norway
* srdjan.djurovic@medisin.uio.no
Recent Genome Wide Association Studies (GWAS) have
revealed novel candidate genes for bipolar disorder, but most
of the genetic mechanisms are still unknown. In the present
study we investigated possible genetic variants of NTRK-3
associated with bipolar disorder in a homogenous Norwegian
sample (the TOP study), based on its important role in brain
development and plasticity and our recently reported findings
for possible association with schizophrenia. We carried
out GWAS of bipolar disorder using the Affymetrix 6.0 array
in case-control samples of Norwegian origin (bipolar disorder
(n=225) , healthy controls (n=385)). Twelve NTRK-3 single
nucleotide polymorphisms (SNPs) were nominally associated
with bipolar disorder. This has been followed by replication in
the available schizophrenia sample and confirmed significant.
The SNPs investigated in the current study are all located in
intronic regions of NTRK-3. Thus, it is difficult to achieve a
full understanding of the effect of the different SNPs on the
level of diagnosis and brain biology. In order to evaluate the
importance of NTRK-3 variants in psychosis, further efforts in
identification of quantifiableclinical (endo)phenotypic
variables are needed.

54 ASSOCIATION ANALYSIS WITH DYSBINDIN
GENE: SHARED GENETIC SUSCEPTIBILITY
BETWEEN BIPOLAR DISORDERS AND
SCHIZOPHRENIA?
A. Ruiz* (1), R. Murray (2), J. Powell (2), E. Miranda (1), P.
Sham (3)
1. Departamento de Psiquiatría, Facultad de Medicina,
Hospital Clínico Universidad de Chile, Santiago, Chile. 2.
Institute of Psychiatry, King’s College London, University of
London. UK 3. Genome Research Center, University of Hong
Kong, Hong Kong.
* airuiz@uchile.cl
Introduction: Recent studies have suggested an overlap in
genetic susceptibility for bipolar disorders and schizophrenia,
including dysbindin gene. Susceptibility alleles for
neuropsychiatric disorders, and patterns of linkage
disequilibrium, are likely to differ in ethnically different
populations. Admixed populations offer an opportunity to
evaluate the role of genetics in the aetiology of complex
disorders. The objective of this study is to carry out an
ssociation analysis of dysbindin gene with schizophrenia and
bipolar disorders in a Chilean admixed population. This paper
will present the results found in the association study between
the dysbindin gene and schizophrenia. Method A case-control
and schizophrenic family samples, according to DSM-IV
criteria, were studied. Five hundred and sixty individuals were
included. Ten dysbindin SNPs, previously associated with
schizophrenia, were genotyped. Markers informative for
ancestry were selected to study the Chilean population
structure. Unphased program was used for the statistical
analysis. Population stratification was studied with L-POP
software. WHAP program was used in the structured
association analysis. Results No single marker and haplotype
associations were detected (p>0.05). The Chilean samples
showed the same pattern of allele frequencies and LD
described for ethnically diverse samples. The analysis of
population structure found two ancestral populations. The
structured association analysis of dysbindin gene, did not
detect possible spurious findings in the Chilean case-control
sample. Conclusion No association between dysbindin gene
and schizophrenia was found. An appropriate interpretation of
the results must consider all possible limitations, including
false results, due to insufficient statistical power, allelic
heterogeneity, and clinical heterogeneity of schizophrenia
55 RGS4 GENE AND SCHIZOPHRENIA: A
CANDIDATE GENE STUDY IN A CHILEAN ADMIXED
POPULATION
A. Ruiz* (1), R. Murray (2), J. Powell (2), E. Miranda (1), P.
Sham (3)
1. Departamento de Psiquiatría, Facultad de Medicina,
Hospital Clínico Universidad de Chile, Santiago, Chile. 2.
Institute of Psychiatry, King’s College London, University of
London. UK 3. Genome Research Center, University of Hong
Kong, Hong Kong.
* airuiz@uchile.cl
Introduction: It has been reported that polymorphisms in the
RGS4 gene, on 1q21-22, are associated with schizophrenia.
This study analysed this possible association in a Chilean
admixed sample, ethnically different from populations
examined in previous reports. Methods: The study was carried
out in a case-control sample, composed of cases with DSM-IV
schizophrenia and unaffected control subjects; and a sample
of DSM-IV schizophrenics families. Five hundred and sixty
individuals were recruited in Santiago, Chile. Four RGS4
markers, previously associated with schizophrenia, and a
number of ancestry informative markers were genotyped. The
data were analysed by means of the UNPHASED program.
Analysis of population stratification, in the case-control
sample, was carried out using L-POP software. A structured
association analysis was performed with WHAP program.
Results: The analysis of population structure detected
stratification in the case-control sample; however the cases
and controls were well matched. Significant LD was observed
for all pairwise calculations. In both samples, none of the
SNPs included in this analysis were found to be associated
with illness (P >0.05), and no significant haplotypic
association was observed (P > 0.05). The structured
association analysis did not show confounding effects of
population stratification. Conclusions: No evidence was found
to support an association between genetic variants in the
RGS4 gene and schizophrenia in this sample; even though the
genetic analysis suggested that the Chilean sample showed
similarities with ethnically different samples, previously
described as having association with this gene. Among other
explanations, these results might be the consequence of
inadequate statistical power.

56 CIRCADIAN POLYMORPHISMS IN NIGHTOWLS
D. Kripke* (1), C. Nievergelt (1), K. Rex (1), W. Klimecki
(2), S. Ancoli-Israel (1), T. Shekhtman (1), J. Kelsoe (1)
1. Department of Psychiatry, University of California, San
Diego 2. Department of Pharmacology, University of Arizona
* dkripke@ucsd.edu
Patients with DSM-IV delayed sleep phase disorder, or
nightowls, have trouble falling asleep until very late at night
and trouble awakening in the morning. This often-disabling
condition is believed to be partially genetic in origin. It has
been hypothesized that polymorphisms in the genes
comprising the intracellular circadian oscillator system may be
involved, as has been demonstrated with the converse
advanced sleep phase disorder. In our sample, delayed sleep
phase disorder is comorbid with both unipolar depression and
bipolar disorder. Cases were 362 mixed-ancestry volunteers
recruited nationally by advertising and interview and 355
ancestrally-balanced controls without any reported disorder of
sleep timing. DNA from blood or saliva samples was
genotyped for 768 SNPs using a custom Illumina Golden Gate
assay. At least some SNPs providing partial tag-SNP
coverage of 36 genes involving the circadian system, its visual
input, and melatonin synthesis were examined. A number of
polymorphisms were nominally associated with DSPS
case-control status, but only rs2482705 in NFIL3 was
significantly associated after control for multiple testing
(nominal P=0.0002, EMP2=0.032, OR=0.46), and that only
among self-identified Europeans, when preliminary controls
for 10 ancestry factors and age were included in the model.
NFIL3 is a negative transcription factor regulating
transcription of several circadian genes and participating in
circadian molecular feedback loops. Since the rare A allele
had an odds ratio of 0.46, it may be protective against delayed
sleep phase or may tend to produce advanced sleep phase.
57 A FAMILY-BASED STUDY OF DNA SEQUENCE
VARIANTS IN GRM7 WITH SCHIZOPHRENIA IN AN
INDONESIAN POPULATION
S. Schwab* (1), C. Ganda (1), N. Amir (2), H. Heriani (2), I.
Irmansyah (2), A. Kusumawardhani (2), M. Nasrun (2), I.
Widyawati (2), D. Wildenauer (1)
1. University of Western Australia 2. University of Indonesia
* sschwab@cyllene.uwa.edu.au
Differences in clinical presentation and outcome of
schizophrenia in patients from developing countries as
opposed to developed countries may suggest the presence of
specific environmental and/or genetic factors. In order to
address this question, we have collected a sample of 124
affected sib-pair families with schizophrenia in Indonesia. We
have used this sample previously for genome wide linkage
analysis and have reported a genome wide significant locus on
chromosome 3p. In our current study we have performed an
association study using single nucleotide polymorphisms
(SNPs) located in the genomic region of the metabotropic
glutamate receptor 7 (GRM7) which is located in the centre of
the linkage peak on chromosome 3p. Overall, 18 SNPs have
been genotyped using fluorescence based genotyping in the
sample of 124 families showing evidence for linkage.
Transmission disequilibrium test revealed one SNP
(rs17031835) with association at a nominal significance level
(P=0.004, not corrected for multiple testing). In addition,
multiple haplotypes containing this SNP showed nominal
significant association as well. Our study supports the idea
that glutamatergic transmission and specifically the GRM7
gene might be important in the development of schizophrenia
in the Indonesian population.

58 INTERACTION OF 5HTTLPR AND DRD4 VNTR ON
SUSTAINED ATTENTION
M. Yamamoto* (1), J. McGeary (1, 2), T. Wells (3), C.
Beevers (3)
1. Brown University Center for Alcohol and Addiction Studies
2. Research Service, Providence Veterans Affairs Medical
Center 3. University of Texas at Austin
* maki_yamamoto@brown.edu
Previous research suggests an association of 5HTTLPR
variation with regards to depression and biased attention to
emotional stimuli. Separate lines of research indicate a similar
association between DRD4 VNTR and attention related
phenotypes. This study aims to examine how these two
variations interact in a population of non-depressed,
un-medicated, healthy adults. Participants completed a
standardized spatial cueing task that assessed maintenance of
attention for happy, sad, fearful, and neutral facial
expressions. Individuals were also genotyped for 5HTTLPR
and DRD4 VNTR polymorphisms. Results indicate a clear
gene x gene interaction for the prediction of maintained
attention. In DRD4 VNTR short homozygotes, an allele dose
pattern is observed such that each additional short 5HTTLPR
allele is associated with increased sustained attention for all
stimuli. However, the pattern is completely reversed for
DRD4 VNTR individuals who carry a seven or greater repeat
allele. Specifically, there is an allele dose response
relationship of decreased attention for each additional short
5HTTLPR allele. These results extend and expand on what
has previously been examined in attentional bias studies. If
replicated, these results suggest the need to jointly model
5HTTLPR and DRD4 VNTR variation in such studies.
59 POLYMORPHISMS IN THE TACR1 GENE ARE
ASSOCIATED WITH
ATTENTION-DEFICIT/HYPERACTIVITY DISORDER
(ADHD), ALCOHOLISM, BIPOLAR DISORDER AND
COMBINED ALCOHOLISM WITH BIPOLAR
DISORDER
S. Sharp* (1), A. McQuillin (1), G. Lydall (1), N. Bass (1), A.
Anjorin (1), M. Marks (1), J. Lawrence (1), M. Morgan (1), P.
Asherson (2), A. Thapar (3), S. Hunt (1), C. Stanford (1), H.
Gurling (1)
1. University College London 2. King's College London 3.
Cardiff University
* s.sharp@ucl.ac.uk
Attention-deficit/hyperactivity disorder (ADHD) is a clinically
and genetically heterogeneous syndrome which is comorbid
with childhood conduct disorder, alcoholism, substance abuse,
dis-social personality disorder, and affective disorders. It is
becoming increasingly clear that genes causing bipolar mania
overlap with genes for a subtype of ADHD. Mice with
functional ablation of the tachykinin receptor 1, TACR1, gene
have recently been proposed as a model of ADHD, presenting
locomotor hyperactivity that is prevented by
psychostimulants. These mice also have reduced voluntary
alcohol consumption, an effect that is mimicked by systemic
administration of the TACR1 antagonist L-703,606 in wildtype
mice. We and others have found evidence of association
between TACR1 and bipolar disorder in three independent
samples. We have also detected association with TACR1
SNPs with ADHD, alcoholism and in combined alcoholism
with bipolar disorder. Increased susceptibility to subtypes of
ADHD, alcoholism and bipolar disorder may be caused by the
same mutations in TACR1. An alternative hypothesis is that
one set of mutations increases the risk for ADHD and that
different sets increase the risk for bipolar disorder and
alcoholism. In an attempt to address this issue, TACR1 in
cases of ADHD and combined alcoholism with bipolar
disorder have been sequenced in order to identify potentially
aetiological changes.

60 HUMAN MINERALOCORTICOID RECEPTOR
GENE VARIANTS MODULATE COGNITIVE
VULNERABILITY FOR DEPRESSION
M. Klok* (1), A. Van der Does (2), E. Giltay (3), F. Zitman
(3), E. De Kloet (1), R. DeRijk (1)
1. Division of Medical Pharmacology, Leiden University,
Leiden/Amsterdam Center for Drug Research (LACDR), The
Netherlands 2. Department of Psychology, Leiden University,
The Netherlands 3. Department of Psychiatry, Leiden
University Medical Center (LUMC), The Netherlands
* m.d.klok@lacdr.leidenuniv.nl
The mineralocorticoid receptor (MR) plays a central role in
the regulation of hypothalamic-pituitary-adrenal (HPA) axis
activity. Animal studies indicate that the MR mediates effects
of cortisol on emotions and coping behaviour. We hypothesise
that human MR-gene variants influence cognition and
emotions. Previously, we showed that a single nucleotide
polymorphism (SNP; MR I180V) related to more feelings of
depression among elderly and identified a MR haplotype
(frequency .36) to relate to higher dispositional optimism in
elderly women, not in men. In the present study 154 students
(46 M/108 F; 23.9±5 yrs) completed a questionnaire that
measures cognitive vulnerability to depression and that
includes subscales for hopelessness, rumination and
aggression (LEIDS-R; Leiden Index of Depression
Sensitivity-Revised). Neuroticism was also measured
(NEO-PI) as well as symptoms of depression (HADS-D). MR
SNPs and haplotypes were assessed, resulting in three
haplotypes with frequencies of .50; .35; .13. Significant
associations were found only in females between the
haplotype with a frequency .35 and lower scores for
hopelessness, aggression, risk aversion, neuroticism (p< .05),
and in particular for rumination (p= .001), persisting after
adjustment for age and emotional abuse during childhood.
Excluding currently depressed participants (n= 14)
strengthened the results. Moreover, this haplotype
significantly associated with less symptoms of depression (p<
.05). The results fit with our previous study showing an
association between this haplotype and higher dispositional
optimism, also only in women. Together the data indicate that
MR-gene variants modulate cognitive vulnerability for
depression. Financial support: Hersenstichting Nederland
(project No. 10F02(2).37), Rivierduinen, KNAW
61 A COLLABORATIVE FAMILY-BASED
ASSOCIATION STUDY OF A GLUTAMATE
RECEPTOR GENE (GRIN2B) IN OBSESSIVE
COMPULSIVE DISORDER.
S. Shaheen* (1), P. Arnold (1), S. Stewart (2), S. Taillefer (3),
E. Yamashita (3), J. Fagerness (3), A. Hounie (4), E. Cook (5),
D. Pauls (2), M. Richter (6), J. Kennedy (7), C. Mathews (8),
G. Hanna (9)
1. Hospital for Sick Children, University of Toronto 2.
Massachusetts General Hospital 3. Hospital for Sick Children
4. University of Sao Paulo 5. University of Illinois at Chicago
6. Sunnybrook Health Sciences Centre 7. Centre for Addiction
and Mental Health 8. University of California at San Francisco
9. University of Michigan
* shaheen70@gmail.com
Obsessive-compulsive disorder (OCD) is a common
debilitating condition affecting 1-3% of the population. Recent
investigation suggests that glutamate, an excitatory
neurotransmitter, may play a critical role in the pathogenesis
of OCD. Specifically, the candidate gene GRIN2B (ionotropic
glutamate receptor NMDA 2B subunit) has been implicated in
OCD based on evidence from neuroimaging and previous
family based association studies. The purpose of this study
was to examine a possible association between SNPs and
haplotype blocks of GRIN2B and OCD in a larger sample that
has been examined previously for this gene. The sample
consisted of OCD-affected probands and their immediate
family members from a combined sample of 1575 individuals
(308 families), recruited from specialized OCD clinics by
investigators at six sites. Tag SNPs were selected (n = 10)
using publicly available databases (dbSNP, HapMap) and the
Haploview program.Genotyping was performed on the
sequenom iPlex platform. Data analysis was performed using
a Family Based Association Test (FBAT) under two models of
inheritance. SNPs rs1019385 (p = 0.04), and rs1806191 (p =
0.04) were significantly associated with OCD transmission in
male probands. A haplotype block consisting of SNPs
rs1806191 and rs1806201 (p < .05) was associated with OCD
transmission in male and female probands. These findings
suggest a possible role of the glutamatergic system,
particularly GRIN2B, in the pathogenesis of OCD.

62 ASSOCIATION OF TRYPTOPHAN
HYDROXYLASE-2 (TPH2) POLYMORPHISM WITH
AGE AT FIRST SUICIDE ATTEMPT IN
PSYCHIATRICALLY ADMITTED ADOLESCENTS
A. Cohen* (1), J. McGeary (2), C. Esposito-Smythers (3), A.
Spirito (4)
1. Department of Biology, Brown University 2. Providence
Veterans Affairs Medical Center, Providence, Rhode Island 3.
Department of Psychology, George Mason University 4.
Center for Alcohol and Addiction Studies, Brown University
* andrew_cohen@brown.edu
Background Tryptophan hydroxylase-2 (TPH2) is the
rate-limiting enzyme in the production of serotonin (5-HT) in
the brain. Genetic variation in the TPH2 gene has been
associated with major depressive disorder, bipolar disorder,
and suicide attempt and completion. However, results so far
are inconclusive. Adolescents represent an at-risk population
for suicide and thus examination of TPH2 variation within an
adolescent sample could provide important information on the
neurobiology underlying suicidal behavior. Methods 90
psychiatrically admitted adolescents (ages 13-17) were
genotyped for TPH2 SNP rs1386494 and associations with
history of a suicide attempt, method of attempt (violent or
non-violent), and age at first attempt were examined for
statistical significance. Results No differences were found
across groups on age, gender, race, or ethnicity. Among
suicide attempters, A carriers were more likely to have a
history of violent suicide attempts than GG homozygotes
(50% vs. 32%, small effect). Conversely, among suicide
attempters, GG homozygotes were more likely to have a
history of non-violent suicide attempts (71% vs. 60%, small
effect). Further, GG homozygotes reported an earlier age at
first suicide (M = 13.2, SD= 2.8) attempt than A carriers (M =
15.2, SD= 1.2) (large effect). No differences were found
across groups on presence of any suicide attempt or total
number of attempts. Conclusion Preliminary results suggest
that variation within the TPH2 gene influences suicide-related
phenotypes. It is possible that TPH2 variation impacts early
brain development that influences suicidal behavior. Further
study of this gene in larger samples is needed to continue this
investigation.
63 HIPPOCAMPAL ATROPHY AS A QUANTITATIVE
TRAIT IN A GENOME-WIDE ASSOCIATION STUDY
(GWAS) IDENTIFYING NOVEL SUSCEPTIBILITY
GENES FOR ALZHEIMER’S DISEASE
S. Potkin* (1), G. Guffanti (1), A. Lakatos (1), J. Turner (1),
F. Kruggel (1), J. Fallon (1), A. Saykin (2), A. Orro (3), S.
Lupoli (3), E. Salvi (3), M. Weiner (4), F. Macciardi (1), A.
Neuroimaging Initiative
1. University of California, Irvine 2. Indiana University 3.
University of Milan 4. University of California, San Francisco
* sgpotkin@uci.edu
INTRODUCTION With the exception of APOE e4 allele, the
common genetic risk factors for sporadic Alzheimer’s Disease
(AD) are unknown. GWAS studies offer the possibility of
discovering unanticipated risk genes. METHOD We
completed a genome-wide association study on 381
participants in the ADNI (Alzheimer’s Disease Neuroimaging
Initiative) study. Samples were genotyped using the Illumina
Human610-Quad BeadChip. 516,645 unique Single
Nucleotide Polymorphisms (SNPs) were included in the
analysis following quality control measures. Two analyses
were completed: a standard case-control analysis, and a novel
approach using hippocampal atrophy measured on MRI as an
objectively defined, quantitative phenotype. A General Linear
Model was applied to identify SNPs for which there was an
interaction between the genotype and diagnosis on the
quantitative trait. RESULTS The case-control analysis
identified APOE and TOMM40 at a genome-wide significance
level of £10-6. The quantitative trait analysis identified 21
genes or chromosomal areas with a p-value £10-6, which can
be considered potential “new” candidate loci to explore in the
etiology of sporadic AD. These candidates included EFNA5,
CAND1, MAGI2, ARSB, and PRUNE2, genes involved in the
regulation of protein degradation, apoptosis, metabolism and
neuronal loss. Supportive evidence based on case-control
studies and biological plausibility by gene annotation is
provided. CONCLUSION Using hippocampal atrophy as a
quantitative phenotype in a genome-wide scan, we have
identified new candidate risk genes for sporadic Alzheimer’s
disease that merit further investigation. A QT analysis
provides a powerful strategy for gene discovery in the context
of a genome-wide survey.

64 A COMMON MECP2 HAPLOTYPE ASSOCIATES
WITH REDUCED CORTICAL SURFACE AREA IN
HUMANS IN TWO INDEPENDENT POPULATIONS
A. Joyner* (1, 2), C. Roddey (1), C. Bloss (1), T. Bakken (1),
L. Rimol (3), I. Melles (3), I. Agartz (3), S. Djurovic (3), E.
Topol (2), N. Schork (2), O. Andreassen (3), A. Dale (1)
1. UCSD 2. STSI 3. TOP
* ajoyner@ucsd.edu
The gene MECP2 is a well-known determinant of brain
structure. Mutations in this gene cause microencephalopathy
and are associated with several neurodevelopmental disorders
that affect both brain morphology and cognition. Though
mutations in MECP2 result in severe neurological phenotypes,
the effect of common variation in this genetic region is
unknown. We find that common sequence variations in a
region in and around MECP2 show association with structural
brain size measures in two independent cohorts, a discovery
sample from the Thematic Organized Psychosis (TOP)
research group, and a replication sample from the Alzheimer’s
Disease Neuroimaging Initiative (ADNI). The most
statistically significant replicated association (p

66 GENETIC VARIATIONS OF FYN-TYROSINE
KINASE IN PSYCHIATRIC DISORDERS
K. Hattori* (1), Y. IIjima (1), H. Uchiyama (1), N.
Yamamoto (1), T. Fujii (1), H. Hori (1), T. Teraishi (1), R.
Hashimoto (2), M. Tatsumi (3), M. Omori (4), N. Okamoto
(4), K. Arima (4), T. Higuchi (5), H. Kunugi (1)
1. Department of Mental Disorder Research, National Institute
of Neuroscience, National Center of Neurology and Psychiatry
2. Molecular Research Center for Children's Mental
Development, Osaka University Graduate School of Medicine
3. Yokohama psychosomatic clinic 4. Department of
Psychiatry, Musashi Hospital, National Center of Neurology
and Psychiatry 5. National Center of Neurology and
Psychiatry
* hattori@ncnp.go.jp
Introduction: Fyn kinase regulates NMDA-R function, and
participates in learning, emotion and sensitivity to
antipsychotics. Recently, we found that Fyn protein levels are
decreased in the platelets of schizophrenic patients (Hattori et
al., 2009). We also found splicing patterns of fyn mRNA are
altered in schizophrenia; specifically, the ratio of a defective
isoform fyn delta-7, in which exon7 was absent, was elevated.
Methods: To determine whether genetic variations of fyn gene
are associated with psychiatric disorders such as schizophrenia
and bipolar disorder, weanalyzed Japanese cohort of 497
patients with schizophrenia, 528 major depression, 138 bipolar
disorder, and 932 control subjects. Eight tagging SNPs were
genotyped by TaqMan assays. A possible association between
the fyn genotype with performance in the Wisconsin Card
Sorting Test (WCST) and intelligence quotient (IQ) was also
examined in 166 control subjects. Results: Although no
association of those SNPs with schizophrenia or depression
was found, a weak but significant association was found
between bipolar disorder and a SNP. Haplotype analyses also
revealed that the frequencies of the haplotype that contain
above SNP were significantly different between bipolar
disorder and the control. Next, among control subjects,
significant differences were observed between two SNPs, both
are on the same LD block, and WCST scores. Conclusion:
Genetic variation of the fyn gene may contribute to molecular
mechanisms of bipolar disorder and some aspects of
intelligence.
67 DIFFERENTIAL GENE EXPRESSION ANALYSIS
BY ACUTE AND CHRONIC LITHIUM TREATMENT
IN HUMAN PRIMARY FIBROBLASTS
C. Fukuhara* (1), S. Lee (1), K. Singhapakdi (2), S. Chen
(3), C. Maddox (4), M. Iuvone (5)
1. Neuroscience Institute, Morehouse School of Medicine 2.
Emory University 3. Department of Dermatology, Emory
University School of Medicine 4. CRC, Morehouse School of
Medicine 5. Department of Ophthalmology, Emory University
School of Medicine
* cfukuhara@msm.edu
One of the difficulties treating psychiatric patients is that some
patients are resistant to certain medications. To help
developing personalized therapies, it would be beneficial to
establish an assay by which clinical sensitivities to medicines
can be evaluated in vitro. For many psychiatric drugs, it takes
several weeks to find out whether or not they will be effective,
a predictive diagnostic test would be useful. Dermal fibroblast
may serve as a convenient model to study the long-term
effects of psychiatric medications because they survive long
enough in vitro for chronic drug experiments without
immortalization, and they express certain transporters and
receptors that are targets of psychiatric medicines. A goal of
the present study was to test the hypothesis that dermal
fibroblasts obtained from human subjects can be used to study
the effects of psychiatric medicines on differential gene
expression patterns among subjects. The mood stabilizer
lithium was used to test for differential gene expression
patterns. Skin biopsies were obtained from healthy volunteers
and fibroblast cell cultures were initiated. Fibroblasts were
cultured in the presence of lithium at 0, 1, or 1.5 mM
concentration for 1 or 4 weeks before harvest. No significant
difference was observed in cell numbers among the three
groups for up to 1 week of the treatments. Total RNA was
isolated from those samples and subjected to Affymetrix
GeneChip Human Genome Array analysis and further real
time quantitative PCR for validation. Our preliminary data
showed that 1738 and 1029 mRNA species were up- and
down-regulated more than two fold by 1-week lithium
treatment. After 4 weeks lithium treatment, 1227 and 962
species were up- and down-regulated. Expressions of about
5000 genes were differentially affected between 1 and 4 weeks
lithium treatments. Consistently over expressed and
suppressed genes between 1 and 4 weeks lithium treatments
were 257 and 180, respectively. Success in establishing the
dermal fibroblast model will enable us to identify biomarkers
that can be used to develop personalized medicines.

68 TRYPTOPHAN HRYDROXYLASE-2 5'- AND
3'-REGULATORY POLYMORPHISMS ARE
DIFFERENTIALLY ASSOCIATED WITH HPA AXIS
FUNCTION AND SELF-INJURIOUS BEHAVIOR IN
RHESUS MONKEY
G. Chen* (1), M. Novak (2), J. Meyer (2), B. Kelly (1), E.
Vallender (1), G. Miller (1)
1. Harvard Medical School 2. University of Massachusetts at
Amherst
* guo-lin_chen@hms.harvard.edu
INTRODUCTION: Tryptophan hydroxylase-2 (TPH2)
synthesizes neuronal serotonin and is linked to numerous
behavioral traits. We have previously identified a constellation
of polymorphisms in rhesus monkey TPH2 (rhTPH2) and
characterized the functionality of3'-UTR polymorphisms. This
study aims to functionally characterize the 5'-FR
polymorphisms and comprehensively evaluate the effect of
rhTPH2 genotype on physiological and behavioral traits.
METHODS: The functionality of rhTPH2 5'-FR
polymorphisms was assessed by luciferase reporter assay,
while the effects of rhTPH2 genotype on
hypothalamic-pituitary-adrenal (HPA) axis function and
self-injurious behavior (SIB) were evaluated by
genotype-phenotype correlation. RESULTS: rhTPH2 5'-FR
haplotype exhibits a significant, cell-dependent effect on gene
expression. The 5'-FR -1485(AT)n polymorphism exerts
significant effects on the afternoon cortisol level and nocturnal
HPA negative feedback, while the 3'-UTR 2051A>C exhibits
significant effects on the morning cortisol level and cortisol
response to ACTH challenge, as well as marginally significant
effects on the daytime HPA negative feedback and self-biting
rate. Meanwhile, -1485(AT)n and 2051A>C interact to
influence the plasma ACTH level. In addition, the
genotype/allele frequency of 5'-FR -1325Ins>Del differed
significantly between self-wounders and non-self-wounders,
while 3'-UTR 2128S>L differed significantly in
genotype/allele frequency between the high- and
low-frequency biters. DISCUSSION: This study demonstrates
the functionality of rhTPH2 5'-FR polymorphisms, and
provides evidence for the differential association of rhTPH2
5'-FR and 3'-UTR polymorphisms with HPA axis function and
SIB. Our findings shed light on the role of TPH2 gene
variance in physiology and behavioral traits, and also
contribute to the understanding of the pathophysiology and
genetics of SIB.
69 CHRNB2 PROMOTER REGION: ASSOCIATION
WITH SUBJECTIVE EFFECTS AND GENE
EXPRESSION DIFFERENCES
N. Hoft* (1), J. Stitzel (1), K. Hutchison (2), J. Miyamoto (1),
M. Ehringer (1)
1. Institute for Behavioral Genetics, University of Colorado,
Boulder, CO, 80309 2. The MIND, Albuquerque, NM 87131
* hoft@colorado.edu
The family of neuronal nicotinic acetylcholine receptors
shows regulation of activity by both endogenous acetylcholine
and exogenous nicotine, making sequence variations in these
receptors likely candidates for association with tobacco
phenotypes. Our group has previously identified a significant
association between a rare SNP, rs2072658,and subjective
effects reported by young adults after smoking their first few
cigarettes (Ehringer et al, 2007). We have replicated this
association in a sample of adult smokers reporting physical
subjective effects after smoking the first of three cigarettes
(1.1mg nicotine) in an experimental session (p=0.01). The
association seems to be driven by sweating, heart pounding
and nausea (p= 0.0075, 0.019, 0.032 respectively). This
suggests variation in CHRNB2 may continue to affect
subjective response long after the initiation period. To assess
whether this SNP, immediately upstream of exon1 of
CHRNB2, and other variation in the promoter region of
CHRNB2 has an effect on gene expression, we cloned 3 kb
upstream of the initiation codon of CHRNB2 into a luciferase
reporter vector. Promoter activity was tested in three cell
types. Preliminary results suggest that in SH-SY5Y and P19
cells, those constructs containing the minor allele of
rs2072658 show reduced expression compared to those
containing the common allele (21% decrease p=0.017 and
19.4% decrease p=0.031 respectively). This difference
indicates rs2072658may lead to functional differences in gene
expression which may contribute to the subjective effects to
nicotine.

70 GENETIC VARIATION IN PROMOTER REGION
OF NPPA GENE IS ASSOCIATED WITH
CARDIOEMBOLIC STROKE
B. Chang (1), J. Kim (1), S. Ko (1), Y. Bu (2), S. Park* (1), J.
Park (1)
1. Kyunghee University 2. Kyunghee University Oriental
Medical Science Center
* sjpark422@khu.ac.kr
Stroke, a complex and multigenic disease, is developed from
the impaired supply of blood to the brain. The obvious genetic
factors or variations which are associated with stroke have
been not found. Atrial natriuretic peptide (ANP; also known as
NPPA) was determined as a genetic factor responsible for
several diseases including stroke. This study genotyped the
single nucleotide polymorphisms (SNP) in promoter region of
NPPA gene using total 941 Koreans of stroke patients
diagnosed from the oriental medicine and controls, and
investigated its association associations. There was no
significant association between four common SNPs and stroke
including hemorrhagic and ischemic and controls. However, in
the Trial of Org 10172 in Acute Stroke Treatment (TOAST)
classification of ischemic stroke, cardioembolic stroke showed
a significant increase in frequency of rs5067(A/G) compared
to contols and small-vessel occlusion (SVO) (p < 0.05).
Considering that natriuretic peptides, as polypeptide hormones
primarily secreted from the heart, play an important role in the
regulation of cardiac hemodynamics, our findings suggest that
a possible association of rs5065C allele in promoter of NPPA
with cardioembolic stroke could regulate the expression of
NPPA gene to develop into stroke. Further study addressed to
the function of rs5067(A/G) is needed. This work was
supported(researched)by the Second Stage of Brain Korea 21
project in 2009.
71 ANALYSIS OF POSITIONAL CANDIDATE GENES
FOR SCHIZOPHRENIA ON CHROMOSOME 5P13
I. Bespalova* (1), B. Ritter (1), G. Angelo (1), J. Hunter (1),
J. Silverman (1)
1. Department of Psychiatry, Mount Sinai School of Medicine,
New York, NY 10029, USA
* irina.bespalova@mssm.edu
We have previously described a large, high-density pedigree
with schizophrenia-affected family members from a genetic
isolate of Spanish origin in the central mountainous region of
Puerto Rico. A genome scan in the extended family revealed a
linkage signal on chromosome 5p13 with a multipoint
lodscore of 4.8. We narrowed the region of linkage to the
minimal critical interval (MCI) of 2.8 Mb, containing 13
annotated genes. We have previously reported on sequencing
of one of these genes, the relaxin/insulin-like family peptide
receptor 3, RXFP3. In the present study we examined all of
the remaining 12 positional candidate genes in MCI by
sequencing their coding, 5’- and 3’-untranslated, and first 2 kb
of putative promoter regions in affected members of the
Puerto Rican family: PDZD2, GOLPH3, MTMR12, ZFR,
SUB1, NPR3, C5orf23, TARS, ADAMTS12, SLC45A2,
AMACR, and C1QTNF3. We detected 100 sequence variants,
61 of which were shared by all affected members of the
family. The shared variants are likely to contribute to the
disorder in the Puerto Rican family. To the time, we have
analyzed the variants detected in the C1q and tumor necrosis
factor related protein 3 (C1QTNF3) gene by genotyping in
unrelated 118 schizophrenia-affected and 136 healthy Puerto
Rican individuals of Spanish origin from the same central
mountainous region of Puerto Rico. None of the
polymorphisms demonstrated an association with the disorder,
suggesting that the genetic variants in C1QTNF3 are most
likely do not play role in schizophrenia.

72 THE EXPRESSION OF THE SCHIZOPHRENIA
CANDIDATE GENE RGS4 IS SUBJECT TO VARIABLE
CIS-ACTING INFLUENCES IN BRAIN
F. Buonocore (1), C. Troakes (1), F. Hill (1), J. Cooper (1), N.
Bray (1)
1. Institute of Psychiatry, King's College London
Regulator of G-protein signaling 4 (RGS4) modulates the
intracellular signalling of several neurotransmitter receptors
implicated in schizophrenia pathophysiology or treatment,
including those binding dopamine, serotonin and glutamate.
The expression of RGS4 in schizophrenic brain has been
reported to be altered at both the RNA and protein level.
Reports of genetic association between non-coding SNPs in
the RGS4 gene and schizophrenia suggest that altered
expression may partly reflect genetic risk factors, and
therefore constitute a primary etiological mechanism in the
disorder. We sought to determine whether RGS4 contains
common variation affecting its expression in human brain,
and, if so, where these effects are manifest. In an initial screen,
we assessed relative allelic expression of RGS4 across
multiple discrete brain regions in 12 individuals. We observed
significant departure from the expected 1:1 ratio of allelic
expression in several individuals, indicating that RGS4 is
indeed subject to common cis-acting regulatory influences in
brain. Furthermore, we found that, within individuals, these
effects varied between brain regions, with more pronounced
allelic expression imbalance in sub-cortical areas. These data
demonstrate the existence of cis-regulatory variation in RGS4,
which could underlie genetic association with schizophrenia,
and point to areas of the brain that are affected.
73 GAB2, GSTP1, SORL1, BDNF, GAPDH AND APOE,
POLYMORPHISMS ASSOCIATED WITH LATE
ONSET ALZHEIMER DISEASE.
G. Izzo (1), O. Forlenza (1), B. Diniz (1), C. Kukita (1), L.
Talib (1), P. Bertolucci (1), W. Gattaz (1), E. Ojopi* (1)
1. Laboratório de Neurociências (LIM 27), Institute of
Psychiatry, University of São Paulo (USP), São Paulo, Brazil
* elida@usp.br
We investigated genes with relevant neurological function
such as oxidative stress, neuronal apoptosis, and neuronal
differentiation in patients with late onset Alzheimer’s Disease
(AD). At the present study, we searched for associations of
late onset AD and 8 single nucleotide polymorphisms (SNPs)
on 5 different genes (GAB2, GSTP1, BDNF, GAPDH, and
APOE). DNA was extracted from AD patients and elderly
controls. We performed genotypic analysis by using allelic
discrimination on real-time PCR. At this time were analyzed
more than 400 subjects. It was found a strong association at
the studied population between the APOE*E2 allele in
controls and also between the APOE*E4 allele in AD patients
(P = 0,00127), confirming data already published. For GAB2
rs2373115 polymorphism, our results suggest that the TT
genotype offers a higher susceptibility for developing AD,
with a strong association (P = 0,005). The other genes studied
did not show any significant association between its genotypes
and AD. Combining APOE*4 allele with all studied
polymorphisms we detected a strong association for some
genotypes. We have analyzed genes involved with relevant
roles in neuronal homeostasis, such as oxidative stress,
neuronal apoptosis and neuronal differentiation. We have
confirmed the APOE*E4 allele and GAB2 rs2373115 ‘TT’
genotype as important targets for development of Alzheimer’s
disease. Our findings confirmed previous data that GAB2
modifies late onset AD risk in APOE*E4 carriers and
influences Alzheimer‘s neuropathology. Although any of the
other genes analyzed has shown a direct association with AD
when compared between patients and controls, it was possible
to observe an association to AD in APOE*E4 carriers,
suggesting a modifying effect of this allele. If those
associations prove to be consistent in larger samples, the
biological roles of these genes on AD will require further
clarification.

COGNITION
74 A GENOME-WIDE ASSOCIATION STUDY OF
NON-PATHOLOGICAL COGNITIVE AGEING
G. Davies* (1), K. McGhee (1) M. Luciano (1), A. Tenesa
(2), A. Payton (3), X. Ke (3), S. Harris (1, 8), A. Gow (1), D.
Liewald (1), L. Whalley (4), H. Fox (5), G. McNeill (6), W.
Ollier (3), A. Pickles (7), D. Porteous (8), P. Visscher (9), J.
Starr (10), M. Horan (11), N. Pendleton (11), I. Deary (1)
1. University of Edinburgh Centre for Cognitive Ageing and
Cognitive Epidemiology, Department of Psychology,
University of Edinburgh, 7 George Square, Edinburgh, UK
2. Colon Cancer Genetics Group, Institute of Genetics and
Molecular Medicine, University of Edinburgh and MRC
Human Genetics Unit, Edinburgh, UK 3. Centre for Integrated
Genomic Medical Research, School of Translational
Medicine, The University of Manchester, Manchester, UK
4. University of Aberdeen Institute of Applied Health
Sciences, Foresterhill, Aberdeen, UK 5. Scottish Dementia
Research Network, Royal Victoria Hospital, Edinburgh, UK
6. Environmental & Occupational Medicine, Liberty Safe
Work Research Centre, Foresterhill Road, Aberdeen, UK
7. Biostatistics Group, Community Based Medicine, SCAN
Building Complex, The University of Manchester,
Manchester, UK 8. Medical Genetics Section, University of
Edinburgh Molecular Medicine Centre and Institute of
Genetics and Molecular Medicine, Edinburgh, UK
9. Genetic Epidemiology, Queensland Institute of Medical
Research, Brisbane, Australia 10. University of Edinburgh
Centre for Cognitive Ageing and Cognitive Epidemiology,
Geriatric Medicine, University of Edinburgh, Royal Victoria
Hospital, Edinburgh, UK 11. Clinical Neurosciences, School
of Translational Medicine, The University of Manchester,
Hope Hospital, Salford, Greater Manchester, UK
* Gail.Davies@ed.ac.uk
Cognitive decline is the single most feared aspect of growing
old. It is a major contributor to lower quality of life and loss of
independence. In the UK, it accounts for 40% of admissions to
institutional care and is currently a major personal and social
burden. Retaining cognitive functions must be a priority for
older people. Cognition and age-related cognitive decline are
determined by genetic and environmental factors. The
heritability of intelligence changes across the lifespan: ~30%
in early childhood to 70% in adulthood and may decline
slightly over the age of 65. This indicates that there are genetic
contributions to individual differences in normal cognitive
ageing. We have taken a hypothesis-free approach and
genotyped two of the largest longitudinal elderly cohorts in the
world that have repeated cognitive test data: ~2,000 samples
from the University of Edinburgh’s and University of
Aberdeen’s follow-up studies of the Scottish Mental Surveys
(SMS) of 1932 and 1947, and ~2,000 DNA samples from the
Dyne Steele DNA bank of University of Manchester Age and
Cognitive Performance Research Centre volunteers (DSDb).
The genetic contribution to cognitive ability traits, and to
age-related change in general cognitive ability, processing
speed, and memory will be studied in the SMS and DSDb
cohorts using simple least squares and assuming an additive
genetic model. The best supported 30 SNPs will be genotyped
in an independent replication set comprising over 6,000
samples. Preliminary analyses have shown possible regions of
interest. Further analyses are in progress and results will be
presented.

75 DECREASE IN IMMEDIATE EARLY GENE
EXPRESSION ONE MONTH AFTER
ELECTROCONVULSIVE SEIZURES.
J. Correia-Pinto (1, 2), J. Quevedo (2), S. Valvassori (3), G.
Feier (3), T. Barichello (3), M. Athie (1), S. Ribeiro (4), W.
Gattaz (1), E. Ojopi* (1)
1. Laboratório de Neurociências (LIM-27), Hospital das
Clínicas, Instituto de Psiquiatria, Faculdade de Medicina da
Universidade de São Paulo, USP, São Paulo, SP, Brazil
2. Laboratório Cesar Timo-Iaria, Instituto de Ensino e
Pesquisa, Hospital Sírio Libanês, São Paulo, SP, Brazil.
3. Laboratório de Neurociências e Instituto Nacional de
Ciência e Tecnologia Translacional em Medicina, Programa
de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica
de Ciências da Saúde, Universidade do Extremo Sul
Catarinense, 88806-000 Criciúma, SC, Brazil. 4. Edmond and
Lily Safra International Institute of Neuroscience of Natal
(ELS-IINN), Natal, RN, Brazil. Federal University of Rio
Grande do Norte (UFRN), Natal, RN, Brazil. Instituto
Nacional de Ciência e Tecnologia em Interfaces
Cérebro-Máquina (INCEMAQ).
* elida@usp.br
Electroconvulsive therapy (ECT) is a commonly used
psychiatric treatment for severe depression management.
Despite its clinical utility, post-ECT memory deficits are a
common side effect. Neuronal plasticity and memory
consolidation are intimately related to the expression of
immediate early genes (IEG) such as Egr1, Fos and Arc. IEG
are rapidly induced in response to extracellular stimuli, and
may thereby initiate an intracellular cascade that underlies
long-term adaptations in neuronal gene expression following
chronic and acute electroconvulsive seizures (ECS), an animal
model of ECT. Here, we examined how acute or chronic ECS,
alter expression of IEGs Egr1, Fos and Arc in hippocampus, a
brain region implicated in the pathophysiology of depression
in humans and in animal models of depression. Forty-two
male Wistar rats, weighting 250–300 mg were submitted to
bilateral ECS. Rats were submitted to a single stimulation
(acute) or to a series of eight stimulations, applied one every
48 hours (chronic). Tissue from hippocampus was collected
immediately after and 2, 7, 30 and 90 days after the last
seizure. Sham-ECS groups were handled as ECS groups but
without shock delivery. Hippocampus from seven animals was
pooled for each time point. Real-time PCR experiments were
performed for Arc, Fos and Egr1, as target genes, and B2m
and Rpl19, as endogenous controls. A fixed-effect ANOVA
was used to account for treatment (acute and chronic) and
temporal effects in gene expression. Then, a one way ANOVA
followed by Tukey’s test as a post-hoc was used for group
comparisons. A significant decrease in expression was
observed for all tested genes comparing chronic versus acute
ECS administration. This decrease was 1.3 fold for Arc
(F1,2=15.895, p=0.001), 1.4 fold for Egr1 (F1,2=13.113,
p=0.001) and 1.5 fold for Fos (F1,2=58.169, p

77 HOW SPECIFIC ARE MATHS QTLS?:
BEHAVIOURAL GENOMIC ANALYSIS.
Y. Kovas* (1), S. Doherty (2), R. Plomin (2)
1. Goldsmiths College
2. SGDP, Institute of Psychiatry, King's College London
*y.kovas@gold.ac.uk
Introduction: Quantitative genetic research has revealed a
strong genetic basis to mathematical ability, and indicates that
largely the same genes contribute to all facets of the
mathematical domain and to other cognitive domains, which
supports a ‘generalist genes’ hypothesis. Our recently
conducted genome wide association scan identified first
quantitative trait loci (QTLs) together explaining 3% in
general mathematical ability (p = 7.277e-14). The association
is linear across the distribution consistent with a quantitative
trait locus (QTL) hypothesis; the third of children in our
sample who harbor 10 or more of the 20 risk alleles are nearly
twice as likely to be in the lowest performing 15% of the
distribution. Our latest analyses, reported here, explore the
associations between these QTLs and other phenotypes
collected as part of Twins Early Development Study. Method:
Using longitudinal multivariate data we examined whether the
SNP-set which explains 3% of the variance in mathematical
ability in our sample at 10 years of age is also associated with
mathematical ability at other ages; and with spatial ability,
reading, and g. The N ranged from 1500 to over 4000.
Results: Although weaker than with mathematical ability at
10, the correlations between the Mathematics SNP Set and
reading, and spatial ability were highly significant.
Conclusions: Our results are consistent with the Generalist
Genes Hypothesis, in that the SNPs found for mathematical
ability are also involved in mathematical disability, in all
components of mathematics tested, and in other cognitive
abilities. Some genetic specificity is also implied by these
results.
DEMENTIA
78 ACE, MTHFR AND APO E GENE POLYMORPHISM
IN NORTH INDIAN PATIENTS WITH ALZHEIMER’S
DISEASE
D. Tewari *(1), U. Mishra (1), J. Kalita (1)
1. Sanjay Gandhi Post Graduate Institute of Medical Sciences,
Lucknow-226014 (INDIA)
*deepshikha_pgi@yahoo.co.in
Background & purpose: Alzheimer disease (AD) is the most
common form of dementia. In the current study we evaluated
the distribution of ACE, MTHFR & APO E genotype in
patients with dementia because of growing interest of
multifactorial etiology of the disease. Methods: The study
group included 80 patients (63 men and 17 women, mean age
78 ± 2.6 years) and 90 normal subjects who visited Neurology
OPD, SGPGIMS, matched according to age and sex, and have
been taken. The dementia status of these patients was assessed
by clinical psychologist using the Clinical Dementia Rating
(CDR) score. These patients were genotyped for vascular
disease–associated polymorphisms in the genes coding for
methylenetetrahydrofolate reductase (MTHFR),
angiotensin-converting enzyme (ACE) and a common genetic
risk factor for AD, apolipoprotein E e4 (APOE e4).
Results: There was no significant association between ACE &
MTHFR genotypes with AD and with control subjects.
However T allele frequency of MTHFR gene is found double
in dementia patients 12.5% (p>0.897) when compared with
controls as 6.2%.There was a higher frequency of APOE e4
alleles in patients with AD (18.2%, P>1.6) compared with
control subjects (1.7%). Conclusions— AD is not associated
with the genetic risk factors for vascular disease examined in
this study.

ENDOPHENOTYPES
79 GENOTYPE-CONTROLLED ANALYSIS OF
PLASMA DOPAMINE beta-HYDROXYLASE IN
CIVILIAN POST-TRAUMATIC STRESS DISORDER
Y. Tang* (1), W. Li (1), K. Mercer (1), B. Bradley (2), C.
Gillespie (1), R. Bonsall (1), K. Ressler (3), J. Cubells (1)
1. Emory University School of Medicine 2. Dept. of
Psychiatry and Behavioral Sciences, Atlanta VA Medical
Center 3. Dept of Psychiatry, Emory University School of
Medicine; Yerkes National Primate Research Center; Howard
Hugh Medical Institute
*ytang5@emory.edu
Background: Norepinephrine (NE) plays multiple roles in
regulating arousal and autonomic stress responses and has
been a central candidate in studying the pathophysiology of
post-traumatic stress disorder (PTSD). Dopamine
β-hydroxylase (DβH) catalyzes the conversion of dopamine
(DA) to norepinephrine (NE). Serum (or plasma) DβH activity
is a highly heritable trait largely under the control of the DBH
locus. Mustapic and colleagues (2007, Am. J. Med. Genet.
Part B 144B: 1087) reported a PTSD-associated deficit in
plasma DβH activity in a genotype-controlled analysis of
combat veterans. We tested whether such a deficit would
occur in a predominantly African American sample of
civilians exposed to a high level of poverty-related stress and
trauma. Methods: The primary outcome measure was severity
of current adult PTSD symptoms, and current DSM-IV
diagnosis of PTSD, as determined by the modified PTSD
Symptom Scale (MPSS). Adulthood trauma exposure was
assessed using the Traumatic Experience Inventory (TEI).
Plasma DβH activity was measured by measuring conversion
of tyramine to octopamine, isolating octopamine by HPLC,
and detecting it by electrochemical detection. Genotypes were
determined using the Taqman® platform. Results: Two
hundred and thirty eight African American subjects were
enrolled in this study. The mean age (± SD) was of 44±13
years, with 57.8% being female. We found a strong
association between rs1611115 genotype and plasma DβH
activity in a co-dominant manner (p0.05) in any genotype group. There
were no significant correlations found between DβH and
PTSD severity and no differences of genotype frequency
between PTSD cases and controls. The current results do not
replicate the findings reported by Mustapic et al (2007) in a
group of combat veterans with and without PTSD.
Conclusions: We have replicated in an African American
sample the prior finding that DBH rs1611115 genotype
strongly associates with DβH activity in a co-dominant
manner. There are no associations between DβH activity and
PTSD diagnosis or symptom severity in this civilian sample.
80 SENSORY GATING ENDOPHENOTYPE AND
NEURONAL OSCILLATORY PATTERNS IN
SCHIZOPHRENIA PATIENTS AND THEIR
UNAFFECTED RELATIVES
M. Hall* (1), A. Gibbs (1), G. Taylor (3), M. Coleman (2), V.
Krause (2), O. Krastoshevsky (2), D. Salisbury (3), D. Levy
(2)
1. Psychology Research Laboratory & Cognitive Neuroscience
Laboratory, McLean Hospital, Harvard Medical School
2. Psychology Research Laboratory, McLean Hospital,
Harvard Medical School 3. Cognitive Neuroscience
Laboratory, McLean Hospital, Harvard Medical School
*mhall@mclean.harvard.edu
P50 sensory gating deficit is a leading endophenotype for
schizophrenia (SZ). The auditory stimulus used to elicit P50
event potentials induces a wide spectrum of oscillatory
responses. Among them, beta-band oscillation (13-30 Hz)
appears to contribute most to auditory P50 gating (Hong et al.,
2008a) 1. However, gating of the beta oscillation was not
impaired in patients with SZ or in their unaffected relatives
(Hong et al., 2008b)2. The relationship between beta-band
gating and P50 gating and the patterns of beta oscillation
responses across brain regions remain to be determined.
51 SZ patients, 25 unaffected first-degree relatives, and 34
healthy comparison subjects were tested using a paired click
paradigm. Evoked power of beta-band responses using time
frequency analyses to S1 and S2 stimuli, gating of beta
oscillatory responses (betaS2/betaS1), and gating of the P50
wave were the main outcome measures. A P50 gating deficit
was found in patients (p=.02). Relatives also showed
moderately reduced suppression compared to controls
(p=.087). Widespread reductions in beta-band responses to
both S1 and S2 stimuli and impairment in gating of beta-band
oscillation were found in patients compared with control
subjects. Relatives did not differ significantly from control
subjects. Correlation between the two gating measures was
low (r =0-0.18).These results suggest that deficits in beta
oscillatory responses are not endophenotypes for SZ. Rather,
these deficits are associated with illness-related factors
including age-of-onset, medication and BPRS scores. The
underlying information processing assessed by the two gating
measures appears to be independent.

81 A GENOME-WIDE LINKAGE STUDY OF
COGNITIVE ENDOPHENOTYPES FOR
SCHIZOPHRENIA HIGHLIGHTS THE
NEUROTROPHIN RECEPTOR GENE (NTRK3) AS A
SUSCEPTIBILITY LOCUS
M. Aukes* (1), B. Alizadeh (2), C. Kemner (1), R. van 't Slot
(1), E. Strengman (1), M. Sitskoorn (3), R. Sinke (2), R. Kahn
(1), R. Ophoff (1)
1. University Medical Center Utrecht 2. University Medical
Center Groningen 3. Tilburg University
*m.aukes@umcutrecht.nl
Integration of multiple lines of evidence is warranted in
complex genetics. Our aim was to find new candidate loci that
contain genes affecting candidate endophenotypes and
potentially schizophrenia. We performed a genome-wide
linkage scan of six schizophrenia endophenotypes with
moderate heritability: sensorimotor gating, openness, verbal
fluency, early visual perception, spatial working memory, and
intelligence. Seven extended multiply affected Dutch
pedigrees (n=118, 649 relative pairs) were genotyped for
6,090 single nucleotide polymorphism markers. Two-point
and multipoint variance-component based linkage analyses
were performed using MERLIN. No genome-wide significant
findings were observed. However, linkage peaks with
suggestive evidence were located at 8q24 for early visual
perception (LOD= 1.8), 17p13 and 16q21-22 for openness
(LOD= 1.7 and 1.5). Suggestive two-point hits (empirical
p-value

83 THE EFFECT OF COMT, BDNF AND NRG1 ON
THE P50 ENDOPHENOTYPE IN PSYCHOSIS
M. Shaikh*(1), M. Hua Hall (2), K. Schulze (1), A. Dutt (1),
I. Williams (1), M. Constante (1), M. Walshe (1), M. Picchioni
(1), T. Toulopoulou (1), D. Collier (1), F. Rijsdijk (1), J.
Powell (1), M. Arranz (1), R. Murray (1), E. Bramon (1)
1. The Biomedical Research Centre for Mental Health at the
Institute of Psychiatry, Kings College London and The South
London and Maudsley NHS Foundation Trust 2. Harvard
Medical School, Psychology Research Laboratory, McLean
Hospital, Belmont
*madiha.shaikh@kcl.ac.uk
Introduction: P50 gating deficits correlate with genetic risk for
schizophrenia and constitute a plausible endophenotype for the
disease. The well-supported role of COMT, BDNF and NRG1
in neurodevelopment and cognition makes a strong theoretical
case for the influence of these genes on P50 endophenotypes.
Methods: The possible role of NRG1, COMT Val158Met and
BDNF Val66Met gene polymorphisms on the P50
endophenotype was examined in a large sample consisting of
psychotic patients, their unaffected relatives and unrelated
healthy controls using linear regression analyses.
Results: No evidence for association between NRG1, COMT
Val158Met or BDNF Val66Met genotype and P50
endophenotype was found. Discussion: The available
neurophysiological evidence suggests that any such
association between P50 indices and NRG1, COMT
Val158Met or BDNF Val66Met genotypes, if present, must be
very subtle.
84 GENETIC AND NEUROCHEMICAL MODULATION
OF BEHAVIOURAL AND NEURAL MEASURES OF
RESPONSE INHIBITION
M. Bellgrove* (1), T. Cummins (1), S. Nandam (1), P. Nathan
(2), J. Wagner (1), J. Mattingley (1), R. Hester (3), C.
Chambers (4)
1. University of Queensland 2. University of Cambridge &
GlaxoSmithKline. 3. University of Melbourne
4. Cardiff University
*m.bellgrove@uq.edu.au
The ability to inhibit behavior is a key aspect of executive
function that allows humans to behave flexibly. Twin studies
have shown that behavioral measures of inhibitory control,
such as stop-signal reaction time (SSRT), are highly heritable,
and inhibitory dysfunction has been touted as a candidate
endophenotype for ADHD and OCD. The neurochemical
substrates of inhibitory control in the human brain remain
unresolved with evidence supporting modulation by
dopamine, noradrenaline and sertonin. We surveyed the
association between a theoretically motivated set of
catecholamine genes, including DAT1, DRD4, DBH, COMT,
DRD2 and NET, and SSRT (SSRT) in a sample of 250
non-clinical adults. Associations were found between markers
on DRD4, DBH and DRD2 that accounted for significant
variance in SSRT, after controlling for age and gender. The
influence of these genetic markers was further investigated in
a targeted fMRI study of inhibitory control in a subset of the
larger cohort (n=50). A further double-blind, placebo
controlled, cross-over study of the influence of an acute
challenge of methylphenidate (30mg), atomoxetine (60mg)
and citalopram (30mg) on SSRT in non-clinical subjects
(n=24) was also conducted. A significant effect of drug
condition was found with inhibitory ability significantly
improved under methylphenidate, compared with all other
conditions. Our genetic, brain imaging and neurochemical data
suggest a prominent role for catecholamine, particularly
dopamine, modulation of inhibitory control but little evidence
for modulation by sertonin.

85 CORTICAL THICKNESS IN SCHIZOPHRENIA
AND BIPOLAR DISEASE: A TWIN MRI STUDY OF
DISEASE-SPECIFIC AND COMORBID
ENDOPHENOTYPES
G. Van Baal* (1), H. Hulshoff Pol (1), H. Schnack (1), R.
Brouwer (1), R. Kahn (1)
1. UMC Utrecht
*G.C.M.vanBaal@umcutrecht.nl
In the last few years, the nosological dichotomy between
schizophrenia and bipolar disease has repeatedly been
challenged by genetic findings. Lichtenstein et al. (The
Lancet, 2009) found substantive heritabilities for both diseases
(64% and 59% respectively), which were mostly due to
comorbid genetic factors (52% of total genetic variance in
schizophrenia, 69% in bipolar disease) and only
partly disease-specific. This strongly encourages research of
endophenotypic traits that shed light on the disrupted
mechanisms responsible for both diseases. Data on cortical
thickness measured on a 1.5 Tesla MRI scanner are
presented, which were collected in a large twin sample of
discordant schizophrenic (MZ/DZ: 12/12), concordant and
discordant bipolar (22/25) and healthy control twin pairs
(45/39), adding up to a total of 330 participants. Large parts of
the cortex were affected differently in schizophrenic
vs. bipolar patients: schizophrenia patients showed thicker
right inferior temporal and sensory-motor cortices than
controls which was accounted for by genetic factors, bipolar
patients showed a thinner right inferior frontal cortex than
controls, which seemed to be due to unique environmental
influences. Other areas were affected in a similar fasion in
both diseases: both types of patients displayed decreased
thickness of parahippocampal gyri, and increased thickness of
left temporoparietal cortex (wernicke's area). In general, these
latter associations were caused by genetic factors. Combined
with a (moderate) heritability, cortical thickness in these
areas may be a promising endophenotype for the genetic
mechanisms of comorbidity of these psychosis-related
diseases.
86 EFFECT OF CACNA1C RS1006737 ON NEURAL
CORRELATES OF VERBAL FLUENCY IN HEALTHY
INDIVIDUALS
V. Nieratschker* (1), A. Krug (2), V. Markov (3), S. Kracht
(2), A. Jansen (2), K. Zerres (4), T. Eggermann (4), T. Stöcker
(5), N. Shah (5), J. Treutlein (6), T. Mühleisen (7), T. Kircher
(2), M. Rietschel (1)
1. Division of Genetic Epidemiology in Psychiatry, Central
Institute of Mental Health, J 5, 68159 Mannheim, Germany
2. Department of Psychiatry and Psychotherapy,
Philipps-University Marburg, Rudolf-Bultmann-Str.
8, 35039 Marburg, Germany 3. Department of Psychiatry and
Psychotherapy, RWTH Aachen University, Pauwelsstr. 30,
52074 Aachen, Germany 4. Institute of Human Genetics,
RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen,
Germany 5. Institute of Neuroscience and Biophysics 3 –
Medicine, Research Center Jülich, Germany 6. Division of
Genetic Epidemiology in Psychiatry, Central Institute of
Mental Health, J 5, 68159 Mannheim, Germany 7. Department
of Genomics, Life & Brain Center, University of Bonn,
Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
*vanessa.nieratschker@zi-mannheim.de
Background: Recent genome-wide association studies
implicated the alpha 1C subunit of the L-type voltage-gated
calcium channel (CACNA1C) gene as a susceptibility locus
for bipolar disorder, schizophrenia and major depression
(Sklar et al., 2008; Ferreira et al., 2009; Green et al., 2009).
While the functions underlying the pathophysiology of these
psychiatric disorders are yet unknown, impaired performance
in verbal fluency tasks is an often replicated finding. We
investigated the influence of the CACNA1C single nucleotide
polymorphism (SNP) rs1006737 on verbal fluency and its
neural correlates. Methods: Brain activation was measured
with functional magnetic resonance imaging (fMRI) during a
semantic verbal fluency task in 63 healthy male individuals.
They additionally performed more demanding verbal fluency
tasks outside the scanner. All subjects were genotyped for
CACNA1C rs1006737. Results: For the behavioral measures
outside the scanner, rs1006737genotype had an effect on
semantic but not on lexical verbal fluency with decreased
performance in risk-allele carriers. In the fMRI experiment,
while there were no differences in behavioural performance,
increased activation in the left inferior frontal gyrus as well as
the left precuneus was found in risk-allele carriers in the
semantic verbal fluency task. Conclusions: The rs1006737
variant does influence language production on a semantic
level in conjunction with the underlying neural systems. These
findings are in line with results of studies in bipolar disorder,
schizophrenia and major depression and may explain some of
the cognitive and brain activation variation found in these
disorders.

87 SYSTEMATIC MUTATION SCREENING STUDY
FOR PPP3CC IN SCHIZOPHRENIA
H. Hwu* (1), C. Liu (1), U. Yang (2), P. Hsu (2), C. Fann (3),
Y. Liu (4), C. Wen (1), C. Chang (3)
1. Department of Psychiatry, National Taiwan University
Hospital, Taipei, Taiwan 2. Institute of Bioinformatics,
National YangMing University, Taipei, Taiwan 3. Institute of
Biomedical Science, Academia Sinica, Taipei, Taiwan 4.
Division of Mental Health and Substance Abuse Research,
National Health Research Institutes, Taipei, Taiwan
* haigohwu@ntu.edu.tw
Protein phosphatase 3 (formerly 2B), catalytic subunit, gamma
isoform (PPP3CC) has been reported associated with
schizophrenia in literature and our previous association tudies.
The aim of the study is to search the risk polymorphisms of
the gene for schizophrenia using systematic mutation
screening method. We have sequenced the exons and promoter
regions of PPP3CC. The samples for direct sequencing are 78
schizophrenic patients and 50 normal controls. We have
identified 22 genetic variations, of which 11 SNPs were
genotyped for further analysis. In a preliminary study of small
sample association study, which included 170 schizophrenic
patients and 144 controls, we found one SNP in the 5’-UTR
and two SNPs in the 3’-UTR region were significantly
associated with schizophrenia either through genotype-wise or
allele-wise analysis. The genotyping work in a large
case-control sample, including 600 normal controls and 912
schizophrenic patients, is ongoing.
88 APPLICATION OF MULTIVARIATE GENETIC
ANALYSIS TO FUNCTIONAL BRAIN IMAGING
A. Scott *(1), K. McNealy (2), M. Dapretto (2), N. Schork (1)
1. Scripps Translational Science Institute 2. University of
California, Los Angeles
*ashleys@scripps.edu
The technologic advances in neuroscience and genetics over
the past decade have dramatically changed the methodological
issues facing neurogenetic researchers. The advent of
high-through put genotyping assays, fine resolution brain
imaging, and in-depth neuropsychological scales have allowed
researchers to acquire massive amounts of data per subject.
The aim of this study was to translate existing multivariate
genetic analysis methods to brain imaging data as a first step
towards an integrated multivariate imaging genetics approach.
Using methods borrowed from analysis of high-dimensional
gene expression data, we analyzed functional magnetic
resonance imaging (fMRI) scans from 18 boys with autism
spectrum disorders (ASD) and 18 age- and IQ-matched
typically developing (TD) boys. Children were scanned while
listening to a well-validated implicit language learning
paradigm (McNealy et al., 2006; McNealy et al. 2009). For
each subject, the mean timeseries from 106 regions-of-interest
(ROI) over the cerebral volume were extracted. Multivariate
distance matrix regression (MDMR; Wessel and Schork,
2006; Schork et al. 2008) identified a number of ROIs
significantly associated with autism diagnosis. Further
examination of these ROIs revealed a subset of regions in
which TD children showed more similar activation profiles
than children with ASD, particularly in language-relevant
areas. These findings are consistent with aberrant language
processing in children with ASD, and demonstrate the
capability of MDMR to identify shared brain activation
patterns across individuals. This method can be extended to
detect shared brain activation patterns among individuals with
similar genetic profiles, providing a foundation for integration
of functional brain imaging data and high-dimensional genetic
data.

89 STRATEGIES FOR PURSUING INTERMEDIATE
PHENOTYPES FOR BIPOLAR DISORDER: THE
HEINZ C. PRECHTER LONGITUDINAL PROJECT
S. Langenecker *(1), M. Kamail (1), L. Franti (1), A. Prossin
(1), E. Saunders (1), A. Vederman (1), M. McInnis (1)
1. University of Michigan Medical School
*slange@med.umich.edu
Introduction: Intermediate cognitive and personality
phenotypes in Bipolar Disorder have been pursued with
somewhat limited success to date. In part, this is due to the
fact that state changes during the course of bipolar illness as
well as high comorbidity with other psychiatric disorders and
subtypes (alcohol and substance abuse, anxiety, psychosis,
attention deficit disorder). Extensive clinical, environmental,
personality and neuropsychological data are gathered from all
participants, including regular follow-up evaluations to
address the possibility of identifying reliable intermediate
phenotypes. Methods: Diagnosis is conducted via structured
Diagnostc interview for Genetic Studies, followed by
Best-Estimate diagnosis in a preliminary cross-sectional
analysis of healthy control subjects (HC, n = 75) and euthymic
(E), depressed (D), or hypomanic/mixed (HM) patients with
bipolar disorder (BD, n = 270). We identified intermediate
cognitive phenotypes (ICPs) and intermediate personality
phenotypes (IPP) from assessments in executive functioning,
attention, memory, fine motor function, emotion processing
and personality. Results: Of the eight cognitive factor scores,
the HC group outperformed the E group in three (Processing
Speed with Interference Resolution, Visual Memory, Fine
Motor Dexterity). Conscientiousness from the NEO-PI was
lower in the D and E groups compared to the HC group. The
E group was higher than the HC group in Neuroticism from
the NEO-PI. Conclusions: Use of the factor scores from
cognitive and personality measures can assist in determining
ICPs and IPPs for BD and related disorders, and may provide
more specific targets for development of new analytic
approaches and treatments.
90 ASSOCIATION OF EVENT-RELATED
OSCILLATIONS AND GLUTAMATE SYSTEM
CANDIDATE GENES
M. Rangaswamy* (1), N. Manz (1), T. Foroud (2), H.
Edenberg (2), B. Porjesz (1), COGA
1. SUNY Downstate Medical Center, Brooklyn, NY 2. Indiana
University, Indianapolis, IN
* madhavi.rangaswamy@downstate.edu
Brain oscillations provide sensitive measures of brain function
with exquisite temporal resolution during cognitive tasks.
These quantitative neurophysiological endophenotypes offer a
powerful tool to study genetics of complex psychiatric
disorders. Event related brain oscillations (EROs) - delta (1-3
Hz) and theta (4-7 Hz) - were recorded during a visual oddball
task from 1312 individuals from 251 multiplex alcoholic
families in the Collaborative Study on the Genetics of
Alcoholism (COGA) sample. Significant linkage (LOD =
3.97) and linkage disequilibrium on chromosome 4 at 139 cM
was detected. Association analysis with a glutamatergic gene
(GRID2) under this linkage peak revealed strong association
with a large number of single nucleotide polymorphisms
(SNPs). The human glutamate receptor gene GRID2 on
chromosome 4, is a member of the glutamate receptor family
which are the predominant excitatory neurotransmitter
receptors in the central nervous system. In a genome-wide
association study (GWAS) based on the Illumina 1 million
SNP array, we analyzed EROs in response to the target
stimulus with the same paradigm in 1064 genetically unrelated
case-control subjects from the COGA study. SNP in several
glutamatergic genomic regions were found to be significantly
associated using a linear regression model for a case-control
study. These findings from both the family based and
case-control studies highlight the involvement of the
glutamatergic pathways associated with cognitive dysfunction
underlying alcoholism.

91 AN ASSOCIATION BETWEEN PREPULSE
INHIBITION AND DRD2 GENE IN A SAMPLE OF
HEALTHY ISRAELIS
M. Monakhov* (1), R. Levin (2), S. Israel (2), U.
Heresco-Levy (2), R. Bachner-Melman (3), R. Ebstein (2)
1. Engelhardt Institute of Molecular Biology, Russian
Academy of Sciences, Moscow, Russia 2. Herzog Memorial
Hospital, Jerusalem, Israel 3. Psychiatry Department,
Hadassah Medical School, Hebrew University , Jerusalem,
Israel
* misha.monahov@gmail.com
Introduction: Prepulse inhibition (PPI) is well-established
measure of sensorimotor gating, that has been associated
with a number of phenotypes including social behavior and
schizophrenia. It reflects the brain’s ability to filter incoming
information of different sensory modalities and so might
indirectly affect social decision making. Some studies report
that D2 dopamine receptor agonists may decrease PPI in
rodents and humans. We performed an association study of
PPI and four SNPs from human DRD2gene. Methods
Prepulse inhibition of the startle response to auditory stimuli
was measured in 38 healthy volunteers (20 males, 18 females;
mean age 26±3.7 years) recruited in Jerusalem, Israel.
Prepulse-pulse intervals of 30, 60 or 120 ms (PPI30, PPI60
and PPI120 values, respectively) were used. DNA was
isolated from blood samples of all participants and their
parents, and genotyping of four DRD2 SNPs (rs1800498,
rs1801028, rs6277, rs1800497) was performed with
5'-nuclease assay or high resolution melt assay. Data
Were analyzed with ANOVA and transmission disequilibrium
test. Results and discussion:ANOVA of PPI among 38
volunteers revealed an association between rs6277 SNP and
60 ms interval PPI (F=5.4 p=0.009), where CC-homozygotes
demonstrated less inhibition (mean±S.D. is 24.8±10.3) than
T-allele carriers (54.4±3.9; for comparison of T+ vs. T-
groups F=10.51, p=0.003). CC homozygotes also had visibly
lower PPI with 30 and 120 ms interval, but differences did not
reach statistical significance. Haplotype T-C-T-C was
associated with higher 30 ms interval PPI
(family-based UNPHASED analysis chisq=4.92, p=0.027). A
trends in same direction, but not significant associations were
observed for 60 and 120 ms interval tests. Results indicate a
possible role of DRD2 in sensorimotor gating.

EPIGENETICS
93 COMBINING EVIDENCE FOR MATERNAL AND
IMPRINTING EFFECTS FROM MULTIPLE STUDIES
B. Glaser* (1), G. Davey-Smith (1), A. Ades (2)
1. Medical Research Council Centre for Causal Analysis in
Translational Epidemiology and Department of Social
Medicine, University of Bristol 2. Department of Community
Based Medicine, University of Bristol
* B.Glaser@bris.ac.uk
The detection of small-scale genetic effects such as those
exerted by maternal genotype or imprinting is often hampered
by lack of sufficient study power. Joint analysis and
meta-analysis can enhance power through increase in sample
size and has been successfully applied to combine evidence
for allelic and genotypic association. However methods to
combine studies of parental influences such as those
detectable in parent-offspring trios are sparse. We developed a
simple Bayesian approach to derive combined estimates for
maternal and/or imprinting effects from multiple parent-child
trio samples and mother-child pairs. For this, we extended the
single-sample Poisson model for categorical outcomes
(Weinberg et al., 1999) into a multinomial framework. Our
approach accounts for sample heterogeneity through random
effects, allows the combination of different sample designs
and enhances the precision of effects estimates by including
prior information. Using simulations, we studied the proposed
method under different scenarios including varying minor
allele frequencies, and genetic effect sizes for both maternal
and imprinting effects. We will report results comparing fixed
effect and random effects models using simulated and real
data.
94 COMPREHENSIVE DNA METHYLATION
ANALYSIS IN THE HUMAN BRAIN AND ITS
APPLICATION TO PSYCHIATRIC DISEASES
K. Iwamoto* (1), M. Bundo (1), J. Ueda (1), Y. Nakano (1),
M. Oldham (2), W. Ukai (3), E. Hashimoto (3), T. Saito (3),
D. Geschwind (2), T. Kato (1)
1. RIKEN Brain Science Institute 2. University of California
Los Angeles 3. Sapporo Medical University
* kaziwamoto@brain.riken.jp
Altered DNA methylation status in the brain is proposed to be
involved in the pathogenesis of psychiatric diseases. Although
several studies reported altered DNA methylation in the brains
of patients, few considered the effect of cellular heterogeneity
in the brain. We employed the cell-sorter based method for
separation of neuronal and non-neuronal nuclei from
postmortem brain, and have performed comprehensive DNA
methylation analyses using various qualitative and quantitative
techniques including global methylation assay targeting whole
genome and LINE-1 sequences, bead-based array, promoter
tiling arrays as well as extensive bisulfite sequencing analyses.
We found that while non-neuronal nuclei showed similar
DNA methylation pattern to bulk cortex, neuronal nuclei
manifested qualitatively and quantitatively distinctive DNA
methylation patterns. Through the bioinformatic analysis, we
found that genes related to neuronal activity were methylated
in non-neuronal nuclei, while genes expressed in astrocytes
were methylated in neuronal nuclei. Such DNA methylation
differences may contribute to the phenotypic differences
between neurons and non-neurons. We are performing a
large-scale case-control study using these techniques.

95 MAPPING GENE REGULATORY ELEMENTS FOR
BRAIN EXPRESSED GENES USING
HIP-SEQUENCING
C. Barr* (1), Y. Feng (1), R. Bremner (1)
1. The Toronto Western Research Institute
* cbarr@uhnres.utoronto.ca
Current evidence indicates that psychiatric disorders are more
likely to result from genetic variation that changes gene
expression rather than variations in the coding region.
However, the role of variation in gene regulation as a
contributor to psychiatric disorders has been largely ignored
because of the difficulty in identifying the location of gene
regulatory elements outside of the proximal promoter. We
used a genome-wide approach to identify brain-relevant gene
regulatory elements, in two cell lines, a neuroblastoma and a
glioblastoma. We used chromatin immunoprecipitation
(ChIP) to modified histones and transcription factors
combined with high throughput sequencing (ChIP-sequencing)
to identify the position of brain-relevant regulatory elements
across the genome. To maximize the identification of
regulatory elements, we performed ChIP using antibodies to
acetylated histone H3, (a marker of active chromatin), the
enhancer-associated protein p300 (a marker of enhancers), and
RNA polymerase II (a marker of regions of active
transcription). This approach was very successful, and we
now have genomic maps of putative regulatory elements for
genes expressed in these cell lines including genes associated
with psychiatric disorders (e.g. DTNBP1, SNAP25). We also
mapped putative gene regulatory elements in gene “deserts”
in the region of positive markers from the GWAS studies. We
are currently screening the putative regulatory regions in
associated genes for genetic variation and testing the
relationship to the respective psychiatric disorder in DNA
from families. We are following on the success of this
approach by identifying regulatory regions in brain tissue,
particularly the DLPFC and the hippocampus.
97 HYPOMETHYLATION OF HTR2A PROMOTER AT
T102C POLYMORPHIC SITE IN DNA DERIVED
FROM THE SALIVA OF PATIENTS WITH
SCHIZOPHRENIA AND BIPOLAR DISORDER
M. Ghadiri* (1), S. Nohesara (1), H. Ahmankhaniha (1), E.
Shirazi (1)
1. Iran University of Medical Sciences
* ghadiri_mohamad@yahoo.com
Introduction: Contribution of the 5HT2A gene in the
pathogenesis of schizophrenia (SCZ) and bipolar disorder
(BD) has been the focus of many studies, because LSD which
resembles serotonin causes psychosis and atypical
antipsychotic drugs elicit their effects by blocking the
5HT2A receptors. There has been evidence for the role of
5HT2A polymorphism(s) in SCZ and BD pathogenesis.
Furthermore, DNA methylation of HTR2A promoter DNA at
T102C polymorphic site was correlated with the HTR2A
expression level in the human brain. Also, DNA
hypomethylation of this site was reported in the post-mortem
brain of patients with SCZ and BD. Hypothesizing that
epigenetic dysregulation of 5HT2A in peripheral tissues may
be used as a diagnostic/therapeutic marker we analyzed
HTR2A promoter DNA methylation status of DNA derived
from the saliva of patients with SCZ and BD vs. normal
controls (each 16). Method:Bisulfite sequencing was used to
screen the CpG methylation status of the 5HT2A entire
promoter region. qMSP was used to quantify the degree of
cytosine methylation at differentially methylated sites in
individuals carrying the C allele of the HTR2a t102c
polymorphism. Results: Based on bisulfite sequencing,
HTR2A promoter DNA was generally unmethylated in the
DNA derived from the saliva however cytosine at T102C
polymorphic site and neighboring cytosines were partially
methylated both in the patient and controls. qMSP analysis
revealed that this cytosine was significantly hypomethylated
in SCZ and BD versus the control subjects. Conclusion:
Cytosine methylation of HTR2A at T102C polymorphic site in
DNA derived from the saliva could be used as a diagnostic,
prognostic and/or therapeutic marker in SCZ and BD.

98 GENOME-WIDE METHYLATION ANALYSIS OF
POSTMORTEM BRAINS SUGGESTS
HYPOMETHYLATION IS ASSOCIATED WITH
MAJOR DEPRESSION
L. Cheng* (1), D. Zhang (1), C. Chen (1), J. Badner (1), W.
Luo (1)
1. Department of Psychiatry and Behavioral Neuroscience,
The University of Chicago
* lcheng2@bsd.uchicago.edu
DNA methylation plays an important role in neuronal
development and differentiation, with potential implications
for neuropsychiatric disease susceptibilities. We performed a
genome-wide methylation study using Illumina Infinium
HumanMethylation27 BeadChip with 27,578 DNA CpG
methylation loci on 153 cerebellum brain DNA samples from
individuals of European ancestry. These samples are from two
collections of the Stanley Medical Research institute and
include 45 Schizophrenia (SZ), 46 Bipolar Disorder (BD), 15
Major Depression (MD) and 47 unaffected control samples.
After removing covariate and batch effects and after
quantile normalization, an ANOVA test was used to detect
differential methylation comparing cases and controls in the
top half CpG loci with high methylation variation. No CpG
locus in SZ, MD and BD show significant difference
compared to controls with FDR q < 0.05. There were
796, 1000 and 706 loci that showed nominally significant
methylation differences with P ≤ 0.05 in SZ, MD and BD
compared to controls, respectively. 33 loci showing
nominally significant methylation changes were shared across
all three diseases. Significantly more hypomethylated
loci in differentially methylated sites were detected in MD (P

GENE X ENVIRONMENT INTERACTIONS
100 GENE-ENVIRONMENT INTERACTION OF THE
LEPTIN RECEPTOR (LEPR) GENE AND TRAUMATIC
LIFE EVENTS MODERATES DEPRESSIVE
SYMPTOMS AND HPA-AXIS FUNCTION
P. Zimmermann (1), T. Brueckl (1), H. Pfister (1), H.
Wittchen (2), F. Holsboer (1), M. Ising (1), S. Lucae (1), R.
Lieb (3), S. Kloiber* (1)
1. Max-Planck-Institute of Psychiatry 2. Technische
Universitaet Dresden
* stkloiber@mpipsykl.mpg.de
The comorbidity of depressive and metabolic disorders led to
the suggestion, that metabolic networks could be involved in
the pathophysiology of depression. Leptin, a major regulator
of metabolic networks and has been shown to influence sleep
and cognition and to exert antidepressant like effects, possibly
via exerting a negative feedback inhibition on the HPA-axis.
In addition, stressful life events, such as trauma, are assumed
to act as environmental triggers for the onset of depression
and, therefore, are capable to moderate the genetic
vulnerability for depression. Analyzing the leptin system
genes (LEP, LEPR, LEPROT, and LEPROTL1; 50 SNPs,
Illumina 550k Bead Chip) in our 10 year prospective
epidemiological sample (EDSP) consisting of 160 nuclear
families including offspring with a lifetime diagnosis of a
major depression (baseline: 3021 individuals aged
14-24 years), we detected SNPs in the LEPR gene displaying a
clear indirect effect on depressive symptoms, which is
moderated by severe traumatic events as environmental risk
factor. Furthermore, the cortisol and ACTH response in the
Dex/CRH test was significantly elevated in depressed patients
carrying the Q223R mutation in a sample of 250 patients with
major depression (MARS). Traumatic events in the patients
history amplified this difference. Results remained significant
after correction for age, gender and multiple testing.
It is conceivable that a malfunctional leptin regulation
influences cortisol levels and glucocorticoid receptor function,
which in turn may contribute to the development of insulin
resistance as well as improper regulation of the HPA axis in
response to stress. While the former increases the risk for
diabetes or other metabolic diseases, the latter poses a risk
factor for the development of depression, especially, in
combination with traumatic events. Our findings, therefore,
provide further evidence that vulnerability for mood disorders
as well as metabolic disturbances might emanate from a
common pathway for which the leptin system might play a
crucial role.
101 INFLUENCE OF CRHR1 POLYMORPHISMS AND
ADVERSE EVENTS ON DEPRESSION AND ANXIETY
IN A COMMUNITY SAMPLE
T. Brückl* (1), M. Ising (1), H. Pfister (1), A. Nocon (1), R.
Lieb (2), F. Holsboer (1), P. Zimmermann (1)
1. Max Planck Institute of Psychiatry 2. University of Basel
* brueckl@mpipsykl.mpg.de
Background: Depression and anxiety are highly comorbid
disorders that can be conceived as stress-related disorders
(SRD). Both disorders are likely to develop after exposure to
stressful life events and are characterized by abnormalities of
the stress hormone regulation. The physical stress
response is mediated by the corticotropin-releasing hormone
(CRH) and polymorphisms in the corticotropin-releasing
hormone type 1 (CRHR1) receptor gene have been implicated
in affective and anxiety disorders (Bradley et al., 2008; Keck
et al., 2008; Liu et al., 2006). The aim of this study is to
examine main and interaction effects of CRHR1
polymorphisms and adverse events on the subsequent onset of
affective and anxiety disorders. Methods: Data come from the
longitudinal-epidemiological Early Developmental Stages of
Psychopathology (EDSP) Study comprising four waves of
data collection (T0-T3) in a randomly selected community
sample of adolescents and young adults aged 14 to 24 years at
baseline and 21 to 34 at third follow-up. Analyses are based
on Caucasian study members who completed the third
follow-up investigation and who consented to participate in
the molecular-genetic part of the study (N=981). DSM-IV
diagnoses and adverse events (e.g., trauma, separation events)
were assessed using the Munich-Composite International
Diagnostic Interview (M-CIDI). The association between prior
adverse event and subsequent affective/anxiety disorder was
assessed through Cox regressions with hazard ratios (HRs)
and time-dependent covariates stratified by sex and age.
Genotyping of the 6 selected SNPs was performed on a
Sequenom platform employing the iPlex technology. Results:
Results showed both an environmental and a genetic main
effect. Prior exposure to an adverse event predicted the
subsequent onset of any affective or anxiety disorder (HR=1.9,
95%CI: 1.5-2.2, p=.000) and heterozygotes of the SNP
“rs242940” reported significantly higher rates of any affective
or anxiety disorder than minor allele homozygotes (45.3% vs.
34.6%, Odds Ratio=1.6. 95% CI: 1.1-2.3, corr. p=.024). We
also found a significant gene-environment interaction for the
same SNP (rs242940) that withstood multiple testing (HR for
interaction = 1.5, 95%CI: 1.1-2.0, corr. p-value=.048): Among
individuals who had experienced an adverse event, carriers of
the minor allele had significantly lower rates of
affective/anxiety disorders than heterozygotes or major allele
homozygotes, while no genotype-dependent differences in the
rate of affective/anxiety disorder could be observed for
individuals without exposure to an adverse event. Conclusion:
CRHR1 polymorphisms seem to moderate the effect of
adverse events on the onset of affective or anxiety disorders
whereby minor allele carriers appear to be protected against
the pathogenic effect of adverse events. Liu Z et al. (2006)
Association of corticotropin-releasing hormone receptor1 gene
SNP and haplotype with major depression. Neuroscience

Letters 404:358-362 Keck M et al. (2008) Combined effects of
exonic polymorphisms in CRHR1 and AVPR1B Genes in a
case/control study for panic disorder. Am J Med Genet Part B
147B:1196-1204. Bradley RG et al. (2008) Influence of child
abuse on adult depression. Arch Gen Psychiatry 65:190-200
102 STRESSFUL LIFE EVENTS AND BDNF IN
BIPOLAR DISORDER
G. Hosang* (1), R. Uher (1), R. Keers (1), N. Craddock (2),
M. Owen (2), A. Korszun (3), L. Jones (4), I. Jones (5), P.
McGuffin (6), A. Farmer (7)
1. Social, Genetic and Developmental Psychiatry Centre,
Institute of Psychiatry, King's College London 2. Cardiff
University 3. Queen Mary, University of London
4.Birmingham University
5. Cardiff University 6. Social, Genetic and Developmental
Psychiatry Centre, Institute of Psychiatry, King's College
London 7. Social, Genetic and Developmental Psychiatry
Centre, Institute of Psychiatry, King's College London
*g.hosang@iop.kcl.ac.uk
Background: Bipolar disorder is a highly heritable illness,
although identification of risk genes remains elusive.
Gene-environment interactions have been the focus of much
research since they are included in the heritability parameter.
The aim of the present study was to examine the interplay
between the BDNF Val66Met polymorphism and stressful life
events (SLEs) in bipolar disorder. Method: A total of 1026
participants were recruited, 440 bipolar I cases and 585
psychiatrically healthy controls. All participants completed
the List of Threatening Life Events Questionnaire, bipolar
subjects reported the events that occurred 6 months leading up
to their worst manic episode and 6 months prior to their worst
depressive episode; controls recorded events experienced 6
months before their interview. The BDNF Val66Met
polymorphism was genotyped for the entire sample. Results.
Both BDNF genotype and SLEs were significantly associated
with bipolar disorder. For the worst depressive episodes the
effects of SLEs was significantly moderated by BDNF
genotype, but only for women. Conclusions: The findings of
this study highlight the importance of the interplay between
genes and the environment in bipolar disorder.
103 WHY GENOTYPE-BY-ENVIRONMENT (GXE)
INTERACTIONS DESERVE MORE ATTENTION: A
LITERATURE REVIEW OF GXE INTERACTIONS IN
PSYCHIATRY
L. Duncan* (1), E. Willcutt (1), M. Keller (1)
1. Institute for Behavioral Genetics, University of Colorado at
Boulder
*Laramie.Duncan@Colorado.edu
Background: Considerable resources have been devoted to
GxE studies and meta-analyses of GxE interactions. However,
to our knowledge, no one has summarized the state of
empirical GxE research from a broader perspective. Method:
Literature review. Results: Across the 46 empirical GxE
studies that met criteria for inclusion in this review, 99
interactions were examined. Fifty-nine percent of the
empirical studies examined one of two interactions:
‘Depression ~ 5-HTTLPR x Stressful Life Events’ OR
‘Antisocial ~ MAOA x Maltreatment’. The former was
generally refuted by meta-analyses, and the latter
supported. Statistically significant interactions in the other
41% of empirical studies involved a wide variety of
phenotypes and environments. However, across all studies,
only ten unique genes were studied, and 96% of genes in
interactions were related to serotonin and/or dopamine
signaling. The pool of participants across studies was
representative for sex, but was not representative of racial and
ethnic diversity in the United States or the world.
Conclusions: Very few unique interactions have been studied,
rendering empirical evidence about the realm of potential GxE
interactions almost non-existent. Therefore, we cannot
conclude that GxE studies “aren’t working” based on
available data. Research dollars would be well-spent
conducting genome-wide by environment studies, attempting
to replicate the most promising GxE studies already
conducted, and analyzing putative GxE interactions in extant
datasets. Attention must be paid to the problem of multiple
testing in GxE research. Additionally, work is needed to
conduct GxE research in genetically diverse samples because
minority populations have been underrepresented.

104 LACK OF EFFECT BETWEEN CANNABIS AND
BDNFVAL66MET POLYMORPHISM INTERACTION
ON THE EMERGENCE OF PSYCHOSIS IN A
POPULATION-BASED SAMPLE.
L. Michelon* (1), G. Busatto (1), R. Murray (2), P. Menezes
(3), M. Scazufca (3), H. Vallada (1)
1. Department of Psychiatry, Universidade de São Paulo
(USP), São Paulo (SP), Brazil 2. Institute of Psychiatry,
University of London, London, UK 3. Department of
Preventive Medicine, Universidade de São Paulo (USP), São
Paulo (SP), Brazil
*lmichelon2@uol.com.br
Background: Brain-derived neurotrophic factor (BDNF) has a
critical role in neurodevelopment, neuroprotection and
cognition. The rs6265 (Val66Met) polymorphism has been
consistently associated with clinical features of
neuropsychiatric disorders. Exposure to cannabis has also
been associated with cognitive deficits and psychosis.
Cannabinoids are known to modulate BDNF serum levels
suggesting associated pathophysiological mechanism
underlying psychosis. Accordingly, this gene-environment
(GE) interaction may be of particular importance for the
emergence of psychosis. Materials and Methods: We
investigated the interaction between cannabis exposure and
BDNF Val66Met polymorphism as a risk for psychosis in an
epidemiological-based series of patients with first onset
psychosis (n=134) recruited in the city of São Paulo/Brazil.
Non-psychotic control subjects (n=191) were randomly
selected from the same geographical areas. Results: Allelic
frequencies for BDNF variants were in Hardy–Weinberg
equilibrium (P>0.05). Psychotic subjects and controls did not
differ in terms of sex, age and ethnic background. We could
not demonstrate any association in this population between
psychosis and BDNF variants. Logistic regression analyzes
showed no GE interactions between cannabis use and
genotype distributions or allele frequencies. The analyses were
controlled for sex, age, ethnic background, scholarship and
partnership. Instead, psychosis was significantly associated
with cannabis exposure (X2 =5.18, p=0.02). Conclusions: The
altered levels of BDNF may reflect the brain damaged caused
by cannabis and not the result of a GE interaction. Despite the
negative findings for rs6265 polymorphism in this population,
gene-cannabis interactions seem to be a reasonable
explanation to its connection with psychosis. Thus, the
mechanisms underlying the association between cannabis and
psychosis may be dependent of other genes variants.
105 ASSOCIATION OF A HAPLOTYPE OF COMT
WITH CANNABIS USE IN A FIRST EPISODE
PSYCHOSIS COHORT
S. Luzi* (1), F. Ducci (1), C. Iyegbe (1), J. Powell (1), R.
Murray (1), M. Di Forti (1)
1. Adult Psychiatry, Institute of Psychiatry, London, United
Kingdom
*sonija.luzi@iop.kcl.ac.uk
Background: Cannabis intoxication can cause brief psychotic
symptoms, whilst chronic abuse has features similar to the
negative symptoms of schizophrenia. An interaction between
cannabis use and the Val458Met polymorphism of COMT has
been reported. The COMT gene is a key enzyme in
catecholamine degradation and the Val458Met polymorphism
has been reported to influence enzymatic activity (Lachman et
al. 1996). Other polymorphisms within the COMT gene have
also been studied. We hypothesized that a haplotype study
may be a more sensitive measure of genetic variation.
Methods: A total of 381 first episode psychosis subjects were
genotyped for four polymorphisms using TaqMan SNP
genotyping assays. Statistical analysis was performed applying
a case only design. Software used: Hapstat, Haploview and
PHASE. Results: Results show an association between a
COMT haplotype and use of cannabis OR 2.02 (± 0.61);
P-Value 0.01. When age of first cannabis use (first use before
or after 16 years of age) was analysed, a more significant
association was found: OR 2.65 (± 1.00); P-Value 0.009. After
the sample was stratified by ethnicity, an association was
observed in the Caucasian group: P-Value 0.04, but not in the
Black Caribbean and African group (P-Value 0.21). No
association between a COMT haplotype and cannabis use was
found in a control group (P-Value 0.78). Conclusions: Our
results suggest an interaction between a COMT haplotype and
cannabis use, particularly when age of first use is during
adolescence. Haplotype studies may capture genetic variations
in the COMT gene more robustly.

GENETIC COUNSELING
106 FAMILIARITY WITH MENTAL ILLNESS AND
FEMALE PATIENTS’ INTEREST IN OBTAINING
RISK ESTIMATES FOR THEIR CHILDREN TO
DEVELOP SEVERE MENTAL ILLNESS
T. Lepard* (1), C. Thrush (1), N. Agan (1), S. Jackson (1)
1. University of Arkansas for Medical Sciences
*tlepard@uams.edu
It has been suggested that as the genetic component of mental
illness (MI) becomes better understood, individuals with a
personal or family history of MI will increasingly become
interested in psychiatric risk assessment for themselves and
their offspring. Several studies have shown a high interest for
psychiatric genetic testing, should it become available.
However, no studies have assessed interest in receiving
empiric risk estimates for offspring to develop MI, which is
available, and who may be interested in learning this
information. This study assessed female participants’ interest
in learning empiric risk estimates for their offspring to develop
MI, and explored associations between this interest and
familiarity with severe MI and other participant
characteristics. A total of 174 women receiving care at a
university based obstetrical/gynecological (Ob/Gyn) clinic
completed the study survey. Most participants (75%) were
somewhat-to-very interested in learning empiric risk estimates
for their offspring, while 25% were not-at-all or only slightly
interested. Overall, a positive correlation existed between
level of familiarity with MI and the desire to learn empiric risk
estimates [rs(174)=0.19, p=0.01]. This correlation was
stronger among participants who were pregnant [rs(114)=0.31,
p=0.001]. Among pregnant participants with a high school
education, there was a large positive association between
familiarity with MI and interest in risk estimates [rs(35)=0.59,
p=0.001], but this correlation was negligible for pregnant
participants who had attended college [rs(78) =0.107,
p=0.35]. Ob/Gyn patients, particularly when pregnant, are
interested in empiric risk estimates for MI in their offspring.
These results should encourage prenatal genetic counselors to
engage their patients in discussion of these empiric risks.
107 GENETIC COUNSELING FOR SCHIZOPHRENIA:
A REVIEW OF REFERRALS TO A PROVINCIAL
MEDICAL GENETICS PROGRAM FROM 1968-2007
M. Hunter (1), C. Hippman (1), W. Honer (1), J. Austin* (1)
1. University of British Columbia
*jehannine.austin@ubc.ca
Introduction: Recent studies have shown that individuals with
schizophrenia and their family members are interested in
genetic counseling, but few have received this service. We
conducted an exploratory, retrospective study to describe (a)
the population of individuals who were referred to the
provincial program for genetic counseling for a primary
indication of schizophrenia, and (b) trends in number of
referrals between 1968 and 2007. Methods: Referrals for a
primary indication of schizophrenia were identified through
the provincial program database. Charts were reviewed and
the following information was recorded: discipline of referring
physician, demographics, psychiatric diagnosis, referred
individual’s and partner’s (if applicable) family history, and
any current pregnancy history. Data was characterized using
descriptive statistics. Results: Between 1968 and 2007, 288
referrals were made for a primary indication of schizophrenia.
Most referrals were made: (a) for individuals who had a
first-degree family member with schizophrenia, rather than for
affected individuals, (b) for preconception counseling, and (c)
by family physicians (69%), with only 2% by psychiatrists.
Conclusions: In British Columbia, individuals affected with
schizophrenia and their family members are rarely referred for
psychiatric genetic counseling. There is a need to identify
barriers to psychiatric genetic counseling and develop
strategies to improve access.

GENETIC EPIDEMIOLOGY
108 FAMILY BASED-ASSOCIATION STUDY
BETWEEN EATING DISORDER AND
SEROTONINERGIC GENES.
B. Camarena* (1), S. Hernández (1), L. Gonzalez (1), A.
Caballero (1)
1. Instituto Nacional de Psiquiatría Ramón de la Fuente
*camare@imp.edu.mx
Evidence from family and twin studies suggests a genetic
contribution in the etiology of eating disorders (ED). The
efficacy of serotonin reuptake inhibitors in the treatment of
ED suggests the serotonin transporter gene (SLC6A4) as a
good candidate for genetic studies. A functional
polymorphism (5-HTTLPR) located on the promoter region
has been associated with basal transcriptional activity levels.
In addition, the 5-HT1Dβ is involved in the regulation of 5-HT
release from serotoninergic neuron terminals in the brain.
Therefore, abnormal function of this auto-receptor could be
involved in the serotonin dysfunction suggested in ED. We
studied two polymorphisms of SLC6A4 and 5-HT1Dβ genes
using a family-based association method. We analyzed 100
families. This sample included 46% with bulimia nervosa,
26% restricting anorexia nervosa and 21% purging anorexia
nervosa subtypes, and 7% EDNOs. The patients showed high
scores of HAM-D and HAM-A. TCI scores showed higher
scores of harm avoidance and lower scores of
self-directedness compared with a control group. Plutchiks
Impulsivity Scale showed high scores in ED patients.
We analyzed the 5-HTTLPR and G861C polymorphisms 100
family trios. Statistical analysis was performed using the
FBAT method. Also, we analyzed clinical phenotypes with
evidence of heritability and relevance to ED, such as BMI,
impulsivity, aggressivity and anxiety. FBAT analysis showed
linkage disequilibrium between 5-HTTLPR and eating
disorders (z=3.01, p=0.0025). Also, FBAT quantitative
analysis showed statistical differences between 5-HTTLPR
and impulsivity (z=2.36, p=0.018) and 5-HT1Dβand anxiety
(z=2.68, p=0.0073). Analysis of alternative phenotypes in
larger samples of informative is necessary to try to find the
gene involves in ED. Acknowledgements: The study was
supported by Pfizer Scientific Institute Grant 2006, México
City.
109 DOWN SYNDROME IN LITHUANIA: SURVIVAL
AND DISABILITY
A. Sinkus* (1), L. Jurkeniene (1), I. Andriuskeviciute (1), G.
Sinkute (1), L. Salomskiene (1)
1. Kaunas Univ. of Medicine
*sinkus@vision.kmu.lt
Every year the medical boards in Lithuania (with the
population 3.4 million people) ascribe about 800
sixteen-year-olds to disablement groups, which makes 1.6% of
the population. Half of these individuals, about 400 people,
are disabled because of severe mental retardation. Each year in
Lithuania 70 babies suffering from Down syndrome are born
but at the age of 16 Down syndrome is diagnosed only for
12-16 individuals (1.8% of disabled patients, or 3.5% of
mentally retarded patients). The specified reasons of death are
usually non-informative in medical histories (“Down
syndrome”, “chromosomal disease”). In other 100 certificates
the following reasons of death were enumerated:
bronchopneumony in 60 patients, acute respirative infection –
in 4, staphylococcous infection -1, tuberculosis -2, congenital
vitium cordis -20, congenital defects of other organs -4,
leukemy -4, accidents -5. In our country we have registered
641 alive Down syndrome patients: 374 children under
16 years of age and 267 adults (two oldest patients were 48
years of age). We have made karyotype analysis in
lymphocyte culture for 393 of them (61.3%). The
chromosomal investigation has confirmed the diagnosis of
Down syndrome in 372 (94.6%) patients. Normal karyotype
was found in 19 (4.8%) patients. In two patients nearby
trisomy-21 an additionally reciprocal translocations of other
chromosomes were present. In two patients chromosome
anomalies other than trisomy-21 were found. The karyotype in
one 3-year-old boy was 49,XXXXY. The boy was deeply
mentally retarded and had mongolian eyeslit, epicanthus,
hypertelorism, palmar simian crease, clinodaktily, arches in
papilar patterns on all ten fingers, and other anomalies typical
of Down syndrome patients. The other chromosome patient
without trisomy-21 was 29-year-old mild mentally retarded
woman in whose karyotype ring chromosome 9 was found.
For both latter patients the physicians suspected Down
syndrome. Therefore, in Lithuanian population false-positive
diagnosis of Down syndrome was found in 5.3% of patients,
i.e. two-three times rarely as compared with analogical
investigations in other countries. We suppose that one of the
reasons of such situation is the racial homogeneity of
Lithuanian population presented almost exclusively by
Caucasians. But in newborn Lithuanian babies the frequency
of false-positive diagnoses arises up to 32.1%: among 134
patients with clinical diagnosis of Down syndrome the normal
karyotype was found in 43. The main clinical feature – mental
retardation – cannot be recognized in infants, and the
neonatologists send the patients for karyotype analysis due to
isolated microanomalies.

110 ASSOCIATION BETWEEN COMT, PTSD, AND
INCREASED SMOKING FOLLOWING HURRICANE
EXPOSURE IN AN EPIDEMIOLOGIC SAMPLE
A. Amstadter* (1), N. Nugent (2), K. Koenen (3), K.
Ruggiero (1), R. Acierno (1), D. Kilpatrick (1), S. Galea (4), J.
Gelernter (5)
1. Medical University of South Carolina 2. Brown Medical
School 3. Harvard University 4. University of Michigan 5.
Yale University
*amstadt@musc.edu
Tobacco smoking has been found to increase after the
experience of a traumatic event and has been associated with
posttraumatic stress disorder (PTSD). Initiation and
persistence of cigarette smoking is moderately heritable; two
recent investigations have implicated the COMT Val158Met
(also known as rs4680) polymorphism in smoking age of
initiation, dependence, as well as in quantity and frequency of
smoking. To examine a possible association of COMT
Val158Met and post trauma increases in cigarette smoking, we
studied 614 adults from the 2004 Florida Hurricane Study who
returned saliva DNA samples via mail. PTSD was strongly
associated with increased smoking. Moreover, each COMT
Val158Met ‘Met’ allele predicted a 2.10 fold risk of smoking
post-hurricane independent of PTSD; follow-up analyses
revealed that this finding was primarily driven by
European-American males. This study represents the first
genetic association study (to our knowledge) of smoking
behavior following an acute stressor.
111 IDENTIFICATION OF LEPTIN, CREB1 AND TPH1
AS CANDIDATE GENES FOR DEPRESSION, OBESITY
AND RELATED COMORBIDITIES IN CASE
CONTROL STUDY AMONG NORTH INDIANS
M. Kapoor* (1), S. Kapur (1), S. Sidhu (2)
1. Birla Institute of Technology and Sciences 2. Guru Nanak
Dev University
*kapoor.manav@gmail.com
Aim: Epidemiological data suggests that there is an
association between obesity and depression, as both disorders
are associated with less control over appetite and increased
risk for metabolic disorders. Present study attempts to find the
common genetic link between these two diseases by looking
into polymorphisms inthe Tryptophan Hydroxylase (TPH),
Leptin (LEP) and CREB1 gene. Methods: This
Exploratory case-control study comprised of 150 clinically
diagnosed depressed individuals and 150 age matched
controls. DNA from all 300 subjects was genotyped for repeat
polymorphisms in leptin gene and CREB1 gene using
PCR-SSLP method, while PCR-RFLP based method was used
for the intronic polymorphism (A218C) in TPH gene. Results:
A significant difference (p

112 A GENETIC ASSOCIATION STUDY OF THE
FUNCTIONAL A118G POLYMORPHISM OF THE
HUMAN OPIOID RECEPTOR GENE AND
IMMUNO-MODULATION IN OPIATE DEPENDENT
SUBJECTS
S. Kapur* (1), S. Sharad (1)
1. Birla Institute of Technology and Science, Pilani,
Rajasthan, India
*mssuman@gmail.com
Purpose: Immunosuppressive effect of opiates is poorly
described and poses a problem in assessing the true spectrum
of these drugs. In this prospective, observational study we
have explored the relationship of variation at the A118G locus
in the Exon 1 of OPRM1 gene, with the amount of opiates
consumed and correlate the immunosuppressive effects of
exogenous opiates with the mu-opiate receptor genotype of the
opiate-dependent and control subjects from northern India.
Methods: Frequency of the wild-type A118 and variant 118G
alleles in dependent subjects (n=73) and age, sex and ethnicity
matched opiate-naïve volunteers (n=73) were examined.
The relationship among the A118G genotype, opiate
consumption and circulating levels of immunoglobilins, IgG
and IgA, were analyzed using linear regression and parametric
tests. Results: Frequency of 118G allele was significantly
lower in control subjects when compared to that observed in
dependent subjects (X2=26.28, p

114 META-ANALYSIS OF GWAS FOR HANDEDNESS:
RESULTS FROM THE ENGAGE CONSORTIUM
S. Medland* (1), C. Lindgren (2), R. Magi (2), B. Neale (3),
E. Albrecht (4), T. Esko (5), D. Evans (6), J. Hottenga (7), M.
Ikram (8), M. Mangino (9), S. Ripatti (10), F. van Rooij (8),
D. Boomsma (7), G. Davey Smith (6), I. Rückert (4), T.
Spector (9), C. van Duijn (8), N. Martin (1), L. Peltonen
(10), M. McCarthy (2). The ENGAGE Handedness
Consortium
1. Genetic Epidemiology, Queensland Institute of Medical
Research, Brisbane, Queensland, Australia 2. Wellcome Trust
Centre for Human Genetics, University of Oxford, Oxford,
UK 3. Center for Human Genetic Research, Massachusetts
General Hospital, Boston, MA USA; 4. Institute of
Epidemiology, Helmholtz Zentrum München, German
Research Center for Environmental Health, Neuherberg,
Germany 5. Institute of Molecular and Cell Biology,
University of Tartu, Tartu, Estonia 6. MRC Centre for Causal
Analyses in Translational Epidemiology, Department of Social
Medicine, University of Bristol, Bristol, UK 7. Department of
Biological Psychology, VU University Amsterdam,
Amsterdam, The Netherlands 8. Dept of Epidemiology,
Erasmus MC, Rotterdam, The Netherlands 9. Dept of Twin
Research & Genetic Epidemiology, King's College, London,
UK 10. National Institute of Health and Welfare, Public
Health Genomics Unit and FIMM, Institute for Molecular
Medicine Finland, Helsinki, Finland.
*sarahMe@qimr.edu.au
Background: Handedness, a consistent asymmetry in skill or
preferential use between the hands, is a moderately heritable
trait which is related to the lateralization of language functions
within the brain. The prevalence of left-handedness (~10% in
the general population) is increased in a number of
psychiatric, neurologic, and learning disorders suggesting that
cerebral asymmetry may play a role in these disorders.
Previous linkage and association studies have had only limited
success. However these studies have used unselected samples
resulting in low numbers of cases and low power. Here we
present the results of a meta-analysis of 12 genome wide
association studies, comprising 23,443 samples (2350 cases,
21093 controls). Methods: Writing hand was used to classify
participants as left- or right-handers, and sex and year of birth
were used as covariates. All samples were derived from
European descent populations. We tested for trait associations
under an additive model for a total of ~2.5 million common
HapMap SNPs (directly genotyped and imputed). Weighted
Z-score based meta-analysis was conducted using METAL
with weights defined by effective sample size. Results: We
observed a number of signals approaching genome-wide
significance (5x10-8) all of which were novel. Promising
results were found on chromosome 5 (p = 2.455e-07) and 13
(p = 6.149e-07), in regions that encompasses SLIT3 (which
plays a role in the axon-guidance-pathways which guide motor
neuronal development during fetal development), MAB21L1
(involved in cerebellum development) and NBEA (which
encodes a neuron-specific multidomain protein implicated in
membrane trafficking that is predominantly expressed in the
brain and during development). Conclusions: No evidence of
association was found for any the traditional asymmetry
candidate genes (NODAL, LEFTY). Large-scale replication
efforts are currently underway. These results vastly extend the
number of loci implicated in the development of handedness
and lateralization in general.

115 THE MGS2 CONTROL SAMPLE: COLLECTION,
CHARACTERIZATION, AND VALIDITY OF A LARGE
SAMPLE OF EUROPEAN-ANCESTRY AND AFRICAN
AMERICAN INDIVIDUALS FOR GENETIC STUDIES
A. Sanders* (1), D. Levinson (2), J. Duan (1), J. Dennis (3),
R. Li (3), K. Kendler (4), J. Rice (5), J. Shi (2), B. Mowry (6),
F. Amin (7), J. Silverman (8), N. Buccola (9), W. Byerley
(10), D. Black (11), R. Freedman (12), C. Cloninger (5), P.
Gejman (1)
1. Center for Psychiatric Genetics, Department of Psychiatry
and Behavioral Sciences, NorthShore University Health
System, Evanston, IL 2. Department of Psychiatry and
Behavioral Sciences, Stanford University, Stanford, CA
3. Government & Academic Research, Knowledge Networks,
Menlo Park, CA 4. Departments of Psychiatry, and Human
Genetics, Virginia Commonwealth University, Richmond, VA
5. Department of Psychiatry, Washington University, St.
Louis, MO 6. Queensland Centre for Mental Health Research,
and Queensland Institute for Medical Research, Brisbane,
Queensland, Australia 7. Department of Psychiatry and
Behavioral Sciences, Atlanta Veterans Affairs Medical Center,
and Emory University, Atlanta, GA
8. Department of Psychiatry, Mount Sinai School of Medicine,
New York, NY 9. School of Nursing, Louisiana State
University Health Sciences Center, New Orleans, LA
10. Department of Psychiatry, University of California at San
Francisco, San Francisco, CA 11. Mental Health Clinical
Research Center, and Department of Psychiatry, University of
Iowa Carver College of Medicine, Iowa City, IA 12.
Department of Psychiatry, University of Colorado Denver,
Aurora, CO
*alan.sanders.md@gmail.com
Background: The Molecular Genetics of Schizophrenia
(MGS2) internet-ascertained an adult control sample of
non-Hispanic European-ancestry (EA, 3,364) and African
American (AA, 1,301) subjects. Methods: By an internet
administered questionnaire (allowing control sample users to
exclude subjects diagnostically similar to their case group), we
collected phenotypic data and then blood samples, both
repository-deposited for general research use. All subjects
were anonymized, and 3,626 comprised the control portion of
the MGS2 genome-wide association study (GWAS) report.
Results: Comparing to the national census, we find the MGS2
control sample is generally representative. The sample is
more female, and somewhat older, more educated and
affluent, but all strata are represented. Self-reported ancestry
matches well to genotypic and census data. Lifetime
diagnostic prevalence estimates for substance, mood, and
anxiety were higher than previous population-based surveys of
psychiatric disorders, probably due to factors such as omission
of data collection for “organic” and other important exclusion
criteria and the anonymity of the survey method. However,
patterns such as sex ratios, comorbidity, relationships to
neuroticism and extraversion, and demographic associations
matched previous reports well. GWAS data cleaning resulted
in equivalent proportions of exclusions for the internet
collected/evaluated control sample compared to the
face-to-face case sample. Conclusions: The results validate
the use of the MGS2 control sample as being generally
representative of the EA and AA U.S. population – for many
aspects of demography, ancestry, and morbidity. The
internet-based methods facilitated data-sharing and sample
utility by enabling rapid collection of a large and
representative sample and anonymization thereof.
116 GENETIC INFLUENCES ON THE NON-MEDICAL
USE OF PRESCRIPTION DRUGS
S. Medland* (1), M. Neale (2)
1. Queensland Institute of Medical Research, Brisbane
Australia
2. Virginia Institute of Psychiatric and Behavioral Genetics,
Richmond USA
*sarahMe@qimr.edu.au
Non-medical use of prescription drugs (PD) is the second most
common form of drug use in teens and young adults, however
relatively little is known about the aetiology of this type of
drug use and the influence of genetic risk factors. We used
family level data collected from twins, sibling and half-sibling
pairs within the Add Health study to examine the magnitude
and relative importance of genetic and environmental
influences on the initiation of PD misuse. The results from this
study indicated that magnitude of genetic influences differed
by drug type. Tranquilizer, Sedative and Stimulant initiation
were moderately heritable ( 40-50%) suggesting that initiation
of these types of prescription drugs are influenced by genetic
risk factors to a similar extent as smoking initiation
(heritability .58 within this sample). However, initiation of
analgesic misuse was found to be predominantly due to shared
and unique environmental influences. Following, from the
initial study, a second series of analyses were conducted using
community level data from the Add Health study. These
multi-level analyses made use of the rich data frame work of
the Add Health study combining data from friendship
networks with the family level data to allow a more detailed
exploration of the environmental influences affecting drug
initiation. These analyses supported the role of genetic
influences on the initiation of Tranquilizers, Sedatives and
Stimulants and showed that friend and community level
environmental influences were more important than within
family influences on the initiation of analgesic misuse. As
analgesic misuse is most common among females, these
results have important implication for the targeting and design
of public health campaigns and interventions.

117 GENOMEWIDE ASSOCIATION STUDY OF
EXTERNALIZING DISORDERS
F. Aliev* (1), M. Ozturk (1), D. Dick (1)
1. Virginia Commonwealth University, Ankara University,
Turkey
*falievfaliev@vcu.edu
Alcohol dependence is commonly comorbid with other
externalizing disorders, including other forms of drug
dependence, antisocial personality disorder, and childhood
conduct disorder. Twin studies indicate that this overlap is due
largely to shared genetic factors that predispose broadly to a
variety of form of externalizing psychopathology (e.g.,
Kendler et al., 2003; Krueger et al., 2000). This has
implications for gene identification efforts, and suggests that
some genes will predispose broadly to a variety of forms of
externalizing problems, rather than being disorder specific.
We have previously shown that analyzing factor scores,
comprised of symptoms of different externalizing disorders
(alcohol dependence, drug dependence, conduct disorder,
antisocial personality disorder), is useful in gene identification
efforts (Dick et al., 2008). Here, we report analyses from the
Collaborative Study on the Genetics of Alcoholism (COGA),
in which a genome-wide association panel was genotyped by
the Center for Inherited Disease Research using the Illumina 1
million SNPchip platforms. Genome wide data was generated
on 2000 individuals, 1905 of which remained after all data
cleaning. All 1205 cases met criteria for DSM-IV Alcohol
Dependence, as assessed by the SSAGA, and all 700 controls
were screened against Alcohol Dependence and related
substance use disorders. We created factor scores indexing
overall externalizing psychopathology, based on
log-transformed symptom counts for alcohol dependence, drug
dependence, conduct disorder, and antisocial personality
disorder. We generated results for overall externalizing factor
scores, as well as for the symptom counts of the individual
disorders used to create the factor scores. We find evidence for
several genes and genomic regions that appear to confer risk
to a variety of forms of externalizing psychopathology.
118 USING LINKAGE INFORMATION TO WEIGHT A
GENOME-WIDE ASSOCIATION OF BIPOLAR
DISORDER
D. Howrigan* (1), J. Smoller (2), P. Sklar (2), S. Purcell (2),
V. Nimgaonkar (3), S. Faraone (4), B. Devlin (3), N. Laird (5),
M. McQueen (1)
1. University of Colorado, Boulder 2. Broad Institute of
Harvard and MIT 3.University of Pittsburgh School of
Medicine 4. SUNY Upstate Medical University, Syracuse,
New York 5. Harvard School of Public Health
*daniel.howrigan@gmail.com
Multiple testing issues in genome-wide association studies
(GWAS) have prompted statistical methods utilizing prior
information to increase the power of association results.
Using prior information derived from genome-wide linkage
studies on Bipolar Disorder, we employed a weighted false
discovery rate (wFDR; Roeder et al., 2006) approach to a
GWAS drawn from the Systematic Treatment Enhancement
Program for Bipolar Disorder (STEP-BD). Using this method,
association signals are up or down-weighted as a function of
the linkage score in that genomic region. Although no SNPs
reached genome-wide significance through the wFDR
approach, the strongest single SNP result from the original
GWAS results, rs4939921 in MYO5B (myosin VB), is
up-weighted as it resides in a region on chromosome 18 that
has a modest linkage signal. We also identify regions on
chromosomes 9, 17, and 18 where clusters of association
signals coincide with linkage evidence, implicating them as
possible candidate regions for further analysis.

EARLY CAREER INVESTIGATOR TRACK:
GENOMEWIDE AND META-ANALYTIC
APPROACHES
ECI 13 GENOME-WIDE ASSOCIATION ANALYSIS OF
THE BECK DEPRESSION INVENTORY LOCALIZES
A QTL INFLUENCING RISK OF MAJOR
DEPRESSIVE DISORDER NEAR THE RND3 GENE
M. Carless* (1), D. Glahn (2), R. Olvera (3), J. Curran (4), H.
Göring (4), T. Dyer (5), E. Moses (5), L. Almasy (5), R.
Duggirala (5), J. Blangero (5)
1. Southwest Foundation for Biomedical Research 2. Yale
University School of Medicine 3. University of Texas Health
Science Center, San Antonio 4. UT Health Science Center,
San Antonio 5. Southwest Foundation for Biomedical
Research
* mcarless@sfbrgenetics.org
Major depressive disorder (MDD) is a common heritable
mental disease for which few susceptibility loci have been
identified. In this study, we describe the first genome-wide
association study to search for genes influencing quantitative
variation in the Beck Depression Inventory (BDI), an
endophenotype measuring depressive severity. Extensive data
has been obtained on 597 individuals from 40 Mexican
American families. Based on a consensus diagnosis following
standardized psychiatric examinations, lifetime prevalence of
MDD was 35% in this population. Heritability of total BDI
(controlling for age and sex effects) was estimated to be 0.27
(p=3.4×10-4), suggesting that approximately one third of the
phenotypic variation in BDI scores has a genetic basis. In
order to localize genomic regions harboring quantitative trait
loci (QTLs) influencing BDI score, we genotyped individuals
using Illumina HumanHap 550K BeadChips. Using a variance
component model incorporating a “measured genotype” fixed
effect, we performed genome-wide association analysis on
BDI, localizing a QTL to chromosome 2q23. One SNP
(rs289943), located between RND3 and FABP5L10 genes,
was strongly associated with BDI (p = 2.1×10-8). This
relatively rare SNP (MAF = 0.05) is also strongly associated
with lifetime MDD affection status (nominal p-value =
8.7×10-4). The RND3 gene may represent an interesting
candidate for risk of depression, coding for a small GTPase
known to be involved neuronal migration and postnatal
development/maturation of the central nervous system and
thought to be involved in the inflammatory response of brain
astrocytes. This result now requires deep sequencing to
identify causal functional variants within this genomic region.
ECI 14 SLEEPLESSNESS SUBPHENOTYPE OF
BIPOLAR I DISORDER HERALDS MORE SEVERE
COURSE OF ILLNESS AND GWAS DATA SUGGESTS
THREE ASSOCIATED GENE VARIANTS
V. Coleman* (1), D. Koller (2), T. Foroud (2), X. Xuei (3), H.
Edenberg (3), X. Cai (4), E. Brizendine (4), M. Erpe (5),
Bipolar Genome Study (BiGS), J. Nurnberger, Jr. (5)
1. Indiana University School of Medicine 2. IUSM,
Department of Medical and Molecular Genetics 3. IUSM,
Department of Biochemical and Molecular Biology 4. IUSM,
Department of Medicine 5. IUSM, Department of Psychiatry
* vecolema@iupui.edu
One strategy for elucidating the genetics and pathophysiology
of bipolar disorder (BPI) involves identification of
subphenotypes; we studied sleeplessness at the onset of mania
as a possible index of circadian disruption. Using diagnostic
data from NIMH Genetics Initiative Bipolar sample (BiGS
Consortium), we performed a case-control study of 2213 BPI
subjects retrospectively reporting sleeplessness preceded their
first manic episode (SLN+; cases) and those who denied such
(SLN-; controls). Genetic analysis using genotypic data of a
SLN+ subset (n=221) versus normal controls (n=1034) was
performed (see Smith, et al, 2009 for detailed methods).
Chi-square tests were performed for categorical data, and
t-tests or Mann-Whitney tests for quantitative variables.
Compared to the SLN- controls, the SLN+ group had more
manic episodes, hospitalizations for mania, suicide attempts,
rapid mood switching and psychosis with mania. Association
was found with two SNPs near KIAA0143, which codes for a
plasma membrane binding protein. The SNPs have a
frequency of ~4% in cases and ~1% in controls. The p-values
for association were 8x10-9 and 2x10-7. Our second area of
interest comprised 3 SNPs near NAP5 (all p=2-4x10-6); this is
designated as a peripheral clock protein and there is a possible
association with multiple sclerosis. A third area of interest
comprised 3 SNPs in MEP1B, the most significant showing a
p-value of 5x10-7. This codes for a zinc metalloprotease.
These results are now being tested in a separate replication
sample. Conclusion: Sleeplessness prior to the first manic
episode may identify a distinct and functional subphenotype
for future investigations.

ECI 15 IDENTIFICATION OF TRAPPC9 AS A CAUSE
OF NON-SYNDROMIC AUTOSOMAL RECESSIVE
MENTAL RETARDATION
L. Kaufman* (1), A. Mir (2), A. Noor (1), M. Ayub (3), J.
Vincent (1)
1. Centre for Addiction and Mental Health (CAMH),
University of Toronto, Toronto, ON, Canada
2. Dept. of Bioscience, COMSATS Institute of Information
Technology, Islamabad, Pakistan
3. St. Luke's Hospital, Middlesborough, United Kingdom
* liana_kaufman@camh.net
In this study, we identify TRAPPC9 as the sixth causal gene
for non-syndromic autosomal recessive mental retardation
(NS-ARMR). Mental retardation is an intellectual disability
characterized by an IQ below 70 and deficits in adaptive
behaviours. Currently, there are only 5 genes known to cause
NS-ARMR. We identified a mutation in TRAPPC9 in a large
consanguineous family from Pakistan with NS-ARMR. Using
5.0 Affymetrix genome wide SNP chips we analyzed the DNA
of 20 family members. We used dChip software to complete
homozygosity mapping, and identified the disease locus at
8q24. Consanguinity makes is possible to identify long
stretches of autozygosity where the disease gene lies. We then
used sequencing to elucidate the disease-causing gene. We
identified a C>T mutation at the end of exon 7 of this 23 exon
gene. The resulting protein contains the nonsense mutation
R377X. Using qPCR we were able to show that the mRNA
levels of TRAPPC9 are markedly decreased in affected family
members. The protein product of TRAPPC9, NIBP, is
involved in the activation of the NF-β signaling pathway. It is
expressed ubiquitously, but at higher levels in the muscle,
heart, brain, kidney, and placenta. It may be involved in
neuronal differentiation and cell survival, as well as in golgi
trafficking. Additional clinical features in affected family
members include cerebellar white matter hypoplasia and
tendency towards small head size. Understanding the genetic
causes for mental retardation is a vital component of
elucidating pathological mechanisms, and other potentially
pathological genes.
ECI 16 COMPREHENSIVE META-ANALYSES BASED
ON ASSOCIATION STUDIES OF ALCOHOL,
COCAINE, HEROIN AND METHAMPHETAMINE
DEPENDENCE
D. Li* (1), H. Zhao (2)
1. Department of Psychiatry, School of Medicine, Yale
University, New Haven, USA 2. Department of Epidemiology
and Public Health and Department of Genetics, School of
Medicine, Yale University, New Haven, USA
* dawei.li@yale.edu
Background: Genetic studies have identified associations of
many susceptibility genes with alcohol, heroin, cocaine,
ormethamphetamine dependence. However, a proportion of
alternative studies have produced contradictory results in
terms of positive and negative findings, possibly reflecting
inadequate statistical power and use of different ethnic
populations. Methods: Using the cumulative case-control and
family-based samples of European, Asian, African, and
Hispanic origins published in recent two decades, the
meta-analyses of 25 commonly-reported candidate genes seek
to examine whether the aggregate data provide evidence of
statistical significance and to clarify the inconsistent findings
using systematic methods and models (eg. allelic vs.
genotypic; dominant vs. recessive; overall vs. sub-grouped;
sensitivity and retrospective analyses; and random effects
model). Results: The serotonin transporter gene (SLC6A4)
was strongly associated with alcohol, heroin, cocaine, and
methamphetamine dependence (P= 0.0002; OR = 0.79 (0.7 -
0.9); Very strong associations were replicated for the aldehyde
dehydrogenase 2 gene (ALDH2) (P = 5 × 10-37; OR = 0.23
(0.18 - 0.29)) and alcohol dehydrogenase genes (P = 2 ×
10-21; OR = 1.9 (1.66 - 2.17) for ADH1B and P = 4 × 10-33;
OR = 2.14 (1.89 - 2.43) for ADH1C) with alcoholism and with
alcohol-induced medical diseases; Strong associations were
detected for the dopamine receptor genes (P = 1 × 10-8for
DRD2 and P = 0.001 for DRD4) and gamma-aminobutyric
acid subunit genes (P = 0.0005 for GABRG2; P = 0.00007 for
GABRA2; and P = 0.00006 for GABRA6) with alcohol and
drug abuse; Significant associations were also found with
5-hydroxytryptamine receptor genes (HTR1B and HTR2A)
and cannabinoid receptor 1 gene (CNR1); Significant
association was also found between the cytochrome P450 2E1
gene (CYP2E1) and alcoholic liver disease (P = 0.007); Strong
association were revealed with the monoamine oxidase A gene
(MAOA, P = 9 × 10-5) and tryptophan hydroxylase gene
(TPH, P = 0.0002) in Caucasians; Weak association was found
with the opioid receptor delta 1 gene (OPRD1); And weak
associations were also revealed with the
catechol-O-methyltransferase gene (COMT) and dopamine
transporter gene (DAT1) in Asians. However, no evidence of
association was found with the DRD1, DRD3, neuropeptide Y
gene (NPY), and OPRM1 genes. No strong evidence of
publication bias was found.Conclusion: The findings in this
study, which may be the most comprehensive meta-analysis
study for substance abuse up to now, may provide the
strongest evidence of associations for these candidate genes.

ECI 17 A GENOME WIDE ASSOCIATION STUDY OF
COMORBID ALCOHOLISM AND BIPOLAR
DISORDER
G. Lydall* (1), N. Bass (1), A. McQuillin (1), M. Robinson
(1), J. Lawrence (1), A. Anjorin (1), R. Kandaswamy (1), A.
Pereira (1), I. Guerrini (1), D. Curtis (2), A. Vine (2), P. Sklar
(3), E. Scolnick (4), S. Purcell (5), H. Gurling (1)
1. Molecular Psychiatry Laboratory, Department of Mental
Health Sciences, Windeyer Institute of Medical Sciences,
University College London, London, UK 2. Centre for
Psychiatry, Barts and the London School of Medicine and
Dentistry, Queen Mary, University of London, UK 3. 6Broad
Institute of Harvard and MIT, Cambridge, MA; 5Departments
of Genetics, Psychiatry or Medicine, Harvard Medical School,
Boston, MA, USA 4. Broad Institute of Harvard and MIT,
Cambridge, MA, USA 5. Departments of Genetics, Psychiatry
or Medicine, Harvard Medical School, Boston, MA; Broad
Institute of Harvard and MIT, Cambridge, MA, USA
* g.lydall@ucl.ac.uk
We have investigated the comorbidity between bipolar
affective disorder and alcoholism with a genome-wide allelic
association study of 506 patients from the University College
London (UCL) bipolar disorder case control sample. In this
group, there were 143 bipolar research subjects who also
had a research diagnostic criteria (RDC) diagnosis of
alcoholism. These were compared to 510 ancestrally-matched
supernormal controls. No marker reached conventional criteria
for genome-wide significance. Genes previously shown to be
associated with alcoholism and addiction phenotypes were
tested for association in the bipolar alcoholic sample using
gene wise permutation tests of all SNPs genotyped within a
50kb region flanking each gene. Several CNS genes showed
significant (p

ECI 19 GENOME-WIDE ASSOCIATION STUDY
IDENTIFIES A RISK LOCUS FOR PEDIATRIC-ONSET
BIPOLAR DISORDER ON CHROMOSOME 5Q
D. Chen* (1), N. Akula (1), C. Steele (1), Bipolar Genome
Study (BiGS), F. McMahon (1)
1. Unit on the Genetic Basis of Mood & Anxiety Disorder,
National Institute of Mental health, National Institutes of
Health, U.S. Dept of Health and Human Services
* chend4@mail.nih.gov
Pediatric-onset bipolar disorder (PBPD) is a strongly familial,
often chronic and disabling condition. The American
Academy of Child & Adolescent Psychiatry (AACAP) defines
PBPD as onset of mania

GENOMICS
119 GENOME-WIDE SCREENING FOR COMMON
AND RARE COPY NUMBER VARIANTS IN A
GERMAN SAMPLE OF BIPOLAR DISORDER
L. Priebe (1), F. Degenhardt (1), S. Herms (1), M. Mattheisen
(1), V. Nieratschker (2), S. Witt (2), R. Breuer (2), M. Alblas
(1), S. Moebus (3), S. Schreiber (4), M. Rietschel (5), M.
Nöthen (6), S. Cichon (6), T. Mühleisen (1)
1. Institute of Human Genetics, Department of Genomics, Life
& Brain Center, University of Bonn, Bonn, Germany 2.
Department of Genetic Epidemiology, Central Institute of
Mental Health, Mannheim, Germany 3. Institute for Medical
Informatics, Biometry and Epidemiology, University Hospital
of Essen, University Duisburg-Essen, Essen, Germany 4.
Institute of Clinical Molecular Biology, University Hospital
Schleswig-Holstein, Kiel, Germany 5. Department of Genetic
Epidemiology, Central Institute of Mental Health, Mannheim,
Germany 6. Institute of Human Genetics, University of Bonn,
Bonn, Germany
Only few studies have investigated the influence of copy
number variants (CNVs) on susceptibility to bipolar
disorder(BP). We conducted a systematic screening for
common and rare CNVs in a sample of 882 patients (~25%
early-onset of BP and/or positive family history) with a
DSM-IV diagnosis of BP I and 872 controls, all of German
descent. They were either genotyped on Illumina's
HumanHap550 or human610-quad arrays, sharing a consensus
set of ~550,000 SNPs. To identify potential CNVs, we used
QuantiSNP and applied a series of quality control and CNV
selection filters. CNVs were compared between patients and
controls by permutation-based tests of association, as
implemented in PLINK. Adopting a global burden approach,
we found no difference in total number of CNVs in patients
vs. controls. However, we observed that patients on average
present larger singleton deletions than controls (patients vs.
controls = 472.6kb vs. 249.3kb; P=0.0139). Furthermore, we
identified three specific CNVs that were nominally associated
with BP: a 224kb deletion on 9q (patients vs. controls = 0.57
% vs. 0%; P=0.032; OR=4.96) and a 160kb duplication on 10q
(patients vs.controls = 6% vs. 3.7%; P=0.035; OR=1.68), and
a 265kb duplication on 6q overrepresented in the early onset
BP disorder subgroup (12/196 patients vs. 22/872 controls =
6.1% vs. 2.5%; P=0.00972; OR=2.52). Our results provide
suggestive evidence for an involvement of large singleton
deletions as well as CNVs on 6q, 9q, and 10q in BP. However,
they need to be followed-up in independent samples before
firm conclusions can be drawn.
120 QUANTITATIVE TRAIT LOCI CONTRIBUTING
TO PHYSIOLOGICAL AND BEHAVIORAL ETHANOL
RESPONSES
E. Drews* (1), I. Racz (1), A. Barth (1), A. Diaz Lacava (2),
A. Bilkei-Gorzo (1), T. Wienker (2), A. Zimmer (1)
1. Institute of Molecular Psychiatry, University of Bonn,
Germany 2. Institute of Medical Biometry, Informatics and
Epidemiology, University of Bonn, Germany
* edrews@uni-bonn.de
The aim of the present study was the identification of gene
loci or quantitative traits that contribute to the development
and manifestation of alcohol addiction and related behaviors.
For a QTL study design the second filial (F2) generation of a
C57BL/6J and C3H/HeJ mice intercross was first phenotyped
in paradigms related to alcohol addiction. We examined
behaviors including ethanol preference, stress-induced
changes in ethanol preference, ethanol-induced hypothermia,
tolerance, somatic withdrawal symptoms, withdrawal-induced
anxiety and locomotor effects in 534 genetically
heterogeneous mice from our intercross. The genotype of
these mice was subsequently assessed by microsatellite marker
mapping accounting fragment lengths polymorphisms between
the alleles of the offspring. QTL contributing to alcohol
dependence and related traits were subsequently identified
using univariate and bivariate analyses. These analyses were
performed with the R/qtl tool, which is an extensible,
interactive environment for mapping QTL in experimental
crosses. To determine individually-acting QTL, a genome scan
using the multiple imputation algorithm was conducted, with a
two-QTL genome scan for the full model (two QTL plus
interaction) and for the additive model (two QTL but no
interaction) interacting loci were analyzed. We detected
chromosomal regions for future exploration where no obvious
candidate gene has yet been mapped. Additionally, we found
QTL that have already been published, thus confirming the
impact of these loci on the development and manifestation of
alcoholism.

121 IDENTIFICATION OF MITOCHONDRIAL DNA
MUTATIONS IN THREE PATIENTS EXHIBITING
NEUROPSYCHIATRIC SYMPTOMS
M. Nakamura* (1), M. Kato (1), M. Ichiba (1), A. Tomiyasu
(1), H. Shimo (1), T. Higuchi (1), S. Ueno (2), A. Sano (1)
1. Departments of Psychiatry, Kagoshima University Graduate
School of Medical and Dental 2. Department of Psychiatry,
Ehime University Graduate School of Medicine, Ehime
University
* nakamu36@m.kufm.kagoshima-u.ac.jp
It has been suggested that mitochondrial dysfunction is an
important factor in the pathogenesis of psychiatric disorders
including depression, schizophrenia and dementia.Recently,
we identified 3 adult patients exhibiting psychiatric symptoms
and mitochondrial encephalopathy who were also shown to
possess mitochondrial DNA (mtDNA) deletion mutations in
their skeletal muscle, but not leukocytes. One patient showing
schizophrenia-like symptoms and dementia was found to carry
a novel polymorphism termed A5127G, which was shown not
to be disease- or schizophrenia-specific. Although
homoplasmic A8291T, which have been reported to be
specific to limb-girdle type mitochondrial myopathy, was also
detected in the patient, the mutation was shown not to be
disease- or schizophrenia-specific. We next investigated
whether mutations or copy number variants existed in the
nuclear genes POLG, POLG2, C10orf2,SLC25A4, ECGF1,
OPA1 and WFS1, as mutations in these genes are known to
cause deletions in mtDNA. We failed to identify any
pathogenic mutations or copy number variants in the 3 patients
observed; however, A587C in SLC25A4was shown to
represent a novel polymorphism not specific to the disease.
Although further studies are required to determine the precise
relationships between novel nuclear gene mutations and
mtDNA mutations, it appears that themolecular pathways
inducing mitochondrial abnormalities may be implicated in a
variety of psychiatric conditions.
122 CONTRIBUTION OF COPY NUMBER
VARIATIONS IN DISC1 AND INTERACTION
PARTNERS TO SCHIZOPHRENIA,
SCHIZO-AFFECTIVE AND BIPOLAR DISORDER IN
THE NORTHERN SWEDISH POPULATION
M. Alaerts (1, 2), L. Moens (1, 2), S. Ceulemans (1, 2), D.
Forero (1, 2), A. Lenaerts (1, 2), K. Norrback (3), D. Goossens
(1, 2), R. Adolfsson (3), J. Del-Favero* (1, 2)
1. 1Applied Molecular Genomics Group, Department of
Molecular Genetics, VIB, Belgium
2. University of Antwerp (UA), Antwerp, Belgium
3. Department of Clinical Sciences, Psychiatry, Umeå
University, Sweden
* jurgen.delfavero@molgen.vib-ua.be
Accumulating genetic and functional evidence support DISC1
as one of the most likely genes to be implicated in the etiology
of schizophrenia(SZ), schizoaffective (SA) and bipolar (BP)
disorders. Furthermore, many of its protein binding partners
show evidence of involvement in the development of these
psychiatric disorders. Since copy-number variation (CNV) is
suspected to play an important causal role in these disorders,
we explored DISC1 and its binding partners PAFAH1B1,
NDE1, NDEL1, FEZ1, MAP1A, CIT and PDE4B for CNVs in
1062 SZ, SA and BPpatients, 227 relatives and 512 unrelated
control individuals from a Northern Swedish isolated
population. This analysis was performed with the
multiplexamplicon quantification (MAQ) method that allows
high resolution CNV detection and resulted in the detection of
three duplications. A rare duplication covering NDEL1 and
part of MYH10 detected in one SZ patientpotentially is a
pathogenic variant with low frequency but high penetrance. A
duplication encompassing NDE1 and adjacent genes might be
a risk factor with small effect for SA disorder. The third is a
relatively common duplication encompassing the first exon of
DISC1, and is not likely to be a susceptibility factor for these
disorders. However, the presence of four copies of this DISC1
CNV, observed exclusively in one patient with SZ, might
nevertheless play a role. Our findings provide further evidence
for involvement of DISC1 and some of its interaction partners
in psychiatric disorders and also for a role of structural
variants in the etiology of these devastating diseases.

123 RESEQUENCING AND COPY NUMBER
VARIATIONS ANALYSES FOR GENES
RESPONSIBLE FOR NEUROACANTHOCYTOSIS IN
MOOD DISORDERS
H. Shimo* (1), M. Nakamura (1), A. Tomiyasu (1), N.
Shiokawa (1), M. Ichiba (1), S. Ueno (2), A. Sano (1)
1. Department of Psychiatry, Kagoshima University Graduate
School of Medical and Dental Sciences, Kagoshima
University 6. Ehime University Graduate School of Medicine
* hishimo7@m2.kufm.kagoshima-u.ac.jp
Neuroacanthocytosis is an inclusive term for a genetically
heterogeneous group of disorders characterized by the
association of neurological and neuropsychiatric abnormalities
with red cell acanthocytosis.The core neuroacanthocytosis
syndromes mainly comprise of the two diseases,
chorea-acanthocytosis(ChAc) and the McLeod
syndrome(MLS). A high incidence of psychiatric disorders
such as mood disorder is known in the patients with ChAc or
MLS and also in carriers with heterozygous pathogenic
mutation of VPS13A, the gene responsible for ChAc, in the
patients’ pedigrees. Thus, we hypothesized that VPS13A
andXK, the gene responsible for MLS, maybe associated with
susceptibility to mood disorder. In the present study, we
performed a comprehensive mutation screen of VPS13A and
XK in 85 patients with mood disorder. We also performed
copy number variations (CNVs) analysis by quantitative PCR
and long range PCR in 72 patients with mood disorder. We
identified four nonsynonymous and eight synonymous single
nucleotide variants that were absent in 50 or more controls.
We identified heterozygous exon60 deletion of VPS13A in
one patient with mood disorder by CNVs analysis. Although
further studies with larger sample size and functional analysis
are needed, present study suggests that
neuroacanthocytosis-related-genes may be associated with
susceptibility to mood disorder.
124 NOVEL PATHOGENIC MUTATIONS AND COPY
NUMBER VARIATIONS OF VPS13A IN PATIENTS
WITH CHOREA-ACANTHOCYTOSIS
A. Tomiyasu* (1), M. Nakamura (1), H. Shimo (1), N.
Shiokawa (1), S. Ueno (2), A. Sano (3)
1. Department of Psychiatry, Kagoshima University Graduate
School of Medical and Dental Sciences, Kagoshima
University, Kagoshima 2. Ehime University Graduate School
of Medicine, Ehime 3. Kagoshima University Graduate School
of Medical and Dental Sciences, Kagoshima University,
Kagoshima
* aki-tomy@m2.kufm.kagoshima-u.ac.jp
Chorea-acanthocytosis(ChAc) is a rare autosomal recessive
neurodegenerative disorder caused by Loss of function
mutations in the VPS13Agene encoding chorein, and
characterized by adult-onset chorea and acanthocytosis in
erythrocytes, psychiatric symptoms such as progressive
cognitive dysfunction. In the present study, we performed
mutational screenincluding sequencing and copy number
variation (CNV) analyses of the VPS13A gene in ChAc
patients. Sequencing analysis was performed for all 73 exons
and flanking regions of VPS13A in 36 patients clinically
diagnosed as ChAc. Since there is a possibility of the
existence of CNVs which fail to be identified by only using
sequencing analysis, we also performed real-time quantitative
PCR for VPS13Agene on patients in whom only one
heterozygous mutation was detected by the sequencing
analysis. We identified 36 different mutations including
disease causing novel CNVs, 27 of which have been
unreported previously. In addition,we investigated the
expression of chorein by the western blot analysis using red
cell ghost samples from some of the patients. Western blot
analysis perfectly demonstrated the absence of chorein in the
patients. We provided the necessity of the real-time PCR as an
accurate, simple, and reproducible method of detecting CNVs
and confirmed an importance of western blot analysis as a
diagnostic method of ChAc.

125 DEVELOPMENT OF NEXT GENERATION
SEQUENCING METHODS FOR TARGETED
SCREENING OF NUMEROUS CANDIDATE GENES IN
MULTIPLE INDEXED DNA SAMPLES TO DETECT
SNPS AND CNVS
D. Morris* (1), E. Kenny (1), A. Gates (1), L. Cochrane (1),
W. Gilks (1), P. Cormican (1), M. Gill (1), A. Corvin (1)
1. Trinity College Dublin
* morrisdw@tcd.ie
Next-generation sequencing technology has allowed
sequencing of whole genomes to be carried out in standard
molecular genetics laboratories. However, an important
application of this technology is sequencing of specific
genomic regions, for example disease genes in patient
samples. In order to sequence parts of the genome of interest,
a number of methods have been developed including long
range PCR and microarray capture. Both methods have been
shown to work but are costly and expensive. Agilent
Technologies have developed the SureSelect Target
Enrichment System. This method allows targeting of 3.3Mb of
the genome by using cRNA baits. Indexing methods have
been developed for next generation sequencing that allow
multiplexing of samples in one sequencing library. We have
combined the SureSelect Target Enrichment System with an
indexing protocol to develop a cost-efficient method for
targeting smaller regions of the genome (e.g. whole genes or
just exons) in multiple DNA samples. We evaluated this
method by sequencing target genes and known copy number
polymorphic regions in HapMap CEU DNA samples and
comparing the results to available online genetic variation
data. For the SureSelect method, unique baits were designed to
capture genomic fragments in the target regions and 3ug of
genomic DNA was used as input for the Illumina genomic
DNA library prep method. The Illumina genomic DNA library
prep method was modified to allow indexing of more than one
sample in each sequencing library according to Craig et al
(2008; PMID: 18794863). Analysis of 9 indexed DNA
samples shows similar and even coverage across target genes
indicating that an indexing method can be combined with the
SureSelect method. We will present data on the performance
of this method in detecting known sequence and structural
variation in HapMap samples and present a protocol that will
be extremely useful in the rapid sequencing of target genomic
regions for SNPs and CNVs in patient and control samples.
126 DETECTION OF STABLE REFERENCE GENES
FOR REAL-TIME PCR ANALYSIS IN
SCHIZOPHRENIA AND BIPOLAR DISORDER
G. Silberberg (1), K. Baruch (1), R. Navon* (1)
1. Department of Human Genetics and Biochemistry, Sackler
School of Medicine, Tel Aviv University, Tel Aviv, Israel
* rnavon@post.tau.ac.il
Gene expression studies using postmortem human brain tissue
are a common tool for studying the etiology of psychiatric
disorders. Quantitative real-time PCR (qPCR) is an accurate
and sensitive technique used for gene expression analysis in
which the expression level is quantified by normalization to
one or more reference genes. Therefore, accurate data
normalization is critical for validating results obtained by
qPCR. This study aimed to identify genes that may serve as
reference in postmortem dorsolateral–prefrontal cortices
(Brodmann’s area 46) of schizophrenics, bipolar disorder
(BPD) patients, and control subjects. In the exploratory stage
of the analysis, samples of four BPD patients, two
schizophrenics, and two controls were quantified using the
TaqMan Low Density Array endogenous control panel,
containing assays for 16 commonly used reference genes. In
the next stage, six of these genes (TFRC, RPLP0, ACTB,
POLR2a, B2M, and GAPDH) were quantified by qPCR in 12
samples of each clinical group. Expressional stability of the
genes was determined by GeNorm and NormFinder. TFRC
and RPLP0 were the most stably expressed genes, whereas the
commonly used 18S, POLR2a, and GAPDH were the least
stable. This report stresses the importance of examining
expressional stability of candidate reference genes in the
specific sample collection to be analyzed.

127 COMPARISON OF FOUR CNV DETECTION
PROGRAMS BASED ON GWAS DATA
D. Zhang* (1), Y. Qian, N. Akula, F. McMahon , C. Liu, E.
Gershon, Bipolar Genome Study (BiGS)
1. University of Chicago
* dandanz@uchicago.edu
Methods for detecting Copy Number Variations (CNVs) using
genome wide SNP arrays are frequently not consistent. We
compared four CNV detection methods including Birdsuite,
Partek, HelixTree, and PennCNV-Affy. We systematically
assessed both rare and common CNVs in 1001 Bipolar cases
and 1033 controls of European Ancestry from the Bipolar
Genome Study (BiGS), and common CNVs in 270 HapMap
samples. Quantitative real-time PCR (qPCR) was used to
evaluate a subset of rare and common CNVs identified by the
Affymetrix SNP 6.0 array in BiGs. For singleton deletions,
Birdsuite and Partek had no false positive calls in our tested
regions. At default parameters, HelixTree called twice as
many singletons relative to the other methods, with the highest
predictive error rate (>70%) by qPCR. For two common
duplication regions, each program had a substantial predictive
error rate (>=25%). For one common deletion region, qPCR
validated all deletions called by Canary. However, the other
three programs all had an unusually high error rate (>70%).
We assessed the true detection rate of 893 independently
discovered and validated CNVs from HapMap samples for
each algorithm. Birdsuite is superior to the other three
programs in the detection rate of known CNVs from HapMap
samples. In conclusion, Birdsuite out-performed the other
programs for singletons and common deletions. For common
duplications, all programs had a substantial error rate.
128 HISTONE GENE EXPRESSION PATTERNS IN
DISCORDANT BIPOLAR SIBLINGS
H. Chen (1), M. Burmeister (1), M. McInnis* (1)
1. University of Michigan
* mmcinnis@umich.edu
Histones profoundly influence the structure of the
chromosome and are subsequently likely to significantly affect
the transcriptional activity of regional genes. We
hypothesized that genes coding for histone proteins contribute
to the genetic complexity of bipolar disorder. We studied the
expression pattern of 20,589 gene transcripts in
lymphoblastoid cell lines (LCL) from a sample of 24
discordant bipolar sibling pairs, using the Illumina Bead chip
technology (Human Refseq 8 V2). A paired t-statistic analysis
identified a total of 91 genes with changed expression patterns
in LCLs from bipolar individuals compared to their unaffected
corresponding siblings (false discovery rate controlled at ~
5%). It is striking that among the genes with significant
expression changes, a systematic down regulation was
observed in histone genes located on chromosomes 6p21 and
1q21 in samples from patients compared to that from
corresponding discordant sibling controls. Real time
quantitative reverse transcriptional polymerase chain reaction
assays confirmed the changes in five histone genes selected
for validation. Genetic studies have suggested a bipolar
disorder locus on 6p21. Our results suggest that down
regulation of histone genes on 6p21 may contribute to the
molecular biology of bipolar disorder.

130 INTEGRATED NEXT-GENERATION
SEQUENCING AND ARRAY BASED ANALYSIS OF
GENETIC MODIFIERS IN VELOCARDIOFACIAL
SYNDROME (VCFS)
A. Urban* (1), Y. Zhang (1), D. Palejev (1), R. Haraksingh
(2), J. Korbel (3), M. Snyder (2), S. Weissman (1)
1. Yale University Department of Genetics 2. Yale University
MCDB Department 3. EMBL Heidelberg
* alexander.e.urban@yale.edu
Schizophrenia is a complex disease with a strong genetic
component. Velocardiofacial Syndrome (VCFS) is typically
caused by a 3 Mbp heterozygous deletion on chromosome
22q11 and up to 30% of patients develop schizophrenia or
similar symptoms. This makes VCFS a prime point of entry to
understand the complex genetic etiology of schizophrenia.
However, the search for the modifying genetic variants needed
to differentiate the 30% of the patients with mental disease
from the remaining 70%, with both groups carrying the 3 Mbp
main deletion, has so far stayed incomplete. Earlier we used
High-Resolution CGH (HR-CGH) on NimbleGen 385K
custom arrays to show that the main deletion can substantially
vary in size between patients [Urban, Korbel et al., PNAS 06]
and that there are additional, smaller, CNVs to be found
within the 3 Mbp deletion interval on the non-deleted
chromosome [Korbel, Urban et al., PNAS 07]. Then we
developed HR-PEM (paired-end mapping) [Korbel, Urban,
Affourtit et al., Science 07] (also [Korbel et al., Genome Biol.,
09]) for sequencing based high-resolution CNV analysis, and
identified 22q11 as a hotspot for small CNV/SV. Here we
report on the integrated genome-wide search for modifiers in
VCFS using HR-CGH and HR-PEM in conjunction with array
capture resequencing (ACRes). We are using a custom
designed 385K NimbleGen longmer array to capture a 5 Mbp
locus containing the VCFS region on chromosome 22q11 and
a NimbleGen 2.1M longmer array to capture all exons in the
human genome. We sequence the captured fractions on the
Illumina Genome Analyzer 2, but using the paired-end
protocol to enhance the power of detection and to reach out
from the exons into their regulatory regions. Through this we
can detect any type of genetic variant in the target regions,
from single nucleotide changes to large CNV/SV, and we
correlate and validate the results with HR-CGH data for the
same samples. We have applied this approach to a panel of
VCFS patients, unaffected relatives and controls and have
detected several hundred genetic variants. We also analyze
genome-wide transcriptional activity in cell lines from the
same VCFS patients, using Illumina GA2 based RNA-Seq to
be able to detect intensity of expression as well as variable
splicing, allele specific transcription and novel and non-exonic
transcripts, and can now correlate the RNA-Seq data with the
ACRes data on genetic variation.
131 A COMBINED GENOME-WIDE ASSOCIATION
ANALYSIS OF SCHIZOPHRENIA AND BIPOLAR
DISORDER IN 20,000 INDIVIDUALS
Douglas Ruderfer & Colm O’Dushlaine on behalf of the
International Schizophrenia Consortium
D. Ruderfer (1), C. O'dushlaine* (1), P. Sklar (1), S. Purcell
(1)
1. MGH
* druderfer@chgr.mgh.harvard.edu
Recent family and molecular genetic studies have provided
strong evidence for a substantially shared genetic basis to
schizophrenia (SCZ) and bipolar disorder (BP), the two major
psychotic illnesses. This overlap suggests that a strategy of
combining genome-wide association study (GWAS) data from
studies of both disorders, along with matched controls, could
increase power to detect the shared common variants of small
effect. We combined previously reported GWAS data on
5,854 patients with schizophrenia, 4,737 with bipolar disorder
and 9,303 controls from matching populations. We sought to
identify genetic factors that are shared, and those that are
unique to one of these two diseases, both at specific loci and at
aggregate levels, including genes, pathways and genome-wide.
We report results from a single SNP analysis for the combined
phenotype (SCZ and BP versus controls) and a parallel
analysis of SCZ versus BP, to search for disease-specific and
modifier variants. A second set of analyses looked for
co-occurrence of potentially distinct risk variants in similar
genes and pathways, investigating the possibility that different
risk alleles in the same gene or pathway may predispose to
either SCZ or BP.

132 GENOME-WIDE SCREEN OF COPY NUMBER
VARIANTS (CNVS) IN THE ADNI SAMPLE
G. Guffanti* (1), F. Torri (2), J. Rasmussen (1), F. Kruggel
(1), J. Turner (1), A. Lakatos (1), S. Potkin (1), F. Macciardi
(1)
1. University of California, Irvine 2. University of Milan
* gguffant@uci.edu
Alzheimer’s disease (AD) is the most common
neurodegenerative disorder affecting more than 15 million
people over the age of 65 worldwide. We present the results
from a whole-genome Copy Number Variants (CNVs) study
on the 818 subjects collected in the ADNI project. Our goal
was to detect genomic structural copy-number variants that
may increase the genetic susceptibility to developing AD.
The ADNI sample was genotyped with more than 600,000
SNPs using the Illumina Human610-Quad BeadChip. We
identified CNVs by using Nexus, a CNV calling program that
relies on SNP genotyping signal intensities. Identification of
events overlapping with previously reported CNVs was
performed using the Database of Genomic Variants (Toronto).
After both genotyping and CNV quality control procedures,
we detected 11,694 CNVs in 638 subjects. The range of
frequencies of the CNVs we detected is in accordance with the
trend (rarely more than 10%) reported in worldwide control
populations (Jacobsson et al., 2008). We identified 10,135
deletions, 1,647 of which are homozygous deletions, and
1,559 duplications, including 6 high copies gain CNVs. We
found only one region of overlapping segments homozygously
deleted exclusively in MCI subjects. The gene affected by the
deletion is ME3 that encodes the malic enzyme 3,
NADP(+)-dependent, involved in the pathway of carbon
fixation in the mitochondria metabolism. We previously
identified another mitochondrial gene, TOMM40 associated
with AD risk (Potkin et al., 2009). We present a
comprehensive analysis of the structural variants that may
contribute to the genetic susceptibility to AD.
133 GENETIC POLYMORPHISM OF
N-ACETYLTRANSFERASE 2 GENE IN KOREAN AND
FOUR OTHER POPULATIONS
H. Park* (1), T. Kand (1), H. Shin (1), H. Na (1), M. Chung
(1)
1. Korea Food and Drug Administration
* hjpark@kfda.go.kr
Background and objective : N-acetyltransferase 2 (NAT2) is
responsible for inter-individual variations in the acetylation of
numerous drugs and in the transformation of aromatic and
heterocyclic amines into carcinogenic intermediates. The aim
of this study was to determine the allele frequencies of
polymorphisms of the NAT2 gene, analyze Linkage
Disequilibrium (LD) block and haplotypes in Koreans and
compare them with those of other ethnic groups. Methods :
We analyzed genetic polymorphism in all functional promoter
and exons of the NAT2 gene by direct sequencing of genomic
DNA from 192 healthy Korean subjects; the LD and
haplotypes blocks of these subjects were constructed from
genotype data using an expectation-maximization algorithm.
We compared these allele frequencies, LD block and
haplotype structure with those of other ethnic groups
registered on the International HapMap database. Results and
discussion : We identified 33 polymorphisms including six
novel single nucleotide polymorphisms(SNPs), -10778 T>C,
-10777 A>G, -10351 A>G, -10199 C>T and -10104 G>T in
promoter and 578 C>T in exon2(T193M) in the Korean
subjects tested. All allele frequencies reported in the Koreans
were similar to those of Asians except for one allele
(rs4345600, -9306 A>G), whereas African and European
Groups had different frequencies in exon2. The haplotype
structure and LD block among the five groups also revealed
significant differences. Conclusion : Ethnic differences in the
NAT2 genotype frequencies may be one of the important
factors that affect the cancer incidence and drug toxicity. Our
current observations could be useful in assessing the
susceptibility of different populations to the risk of cancer, as
well as contribute to predicting the pharmacokinetics and
pharmacodynamics of drugs that are metabolized by NAT2.

134 THE ASSOCIATIONS OF NONSYNONYMOUS
SNPS IN CYP4A GENES WITH KOREAN STROKE
PATIENTS
J. Park* (1), Y. Bu (1), S. Park (1), J. Kim (1), S. Ko (1)
1. Kyung-Hee University
* suyahpark@gmail.com
Stroke is affected by genetic factors as well as other diseases
including hypertension and arteriosclerosis. However, the
distinctive association with genetic variations is not
discovered. Recently, 20-hydroxyeicosatetraenoic acid
(20-HETE), which is produced from arachidonic acid by
CYP4A family, has been reported to be associated with
cerebral blood flow. Therefore, to investigate the association
between genetic variations of CYP4A genes and stroke, this
study genotyped five common nonsynonymous variants of
CYP4A11 and CYP4A22 in 674 stroke patients and 267
controls. Each variant showed no significant association with
stroke and its subtypes, such as hemorrhagic, ischemic and
TOAST classification. However, a haplotype of CGC, which
is composed of rs12564525C/T, rs2056900G/A,
rs10789501T/C SNPs in CYP4A22, showed a significant high
frequency in hemorrhagic group. In addition, it was found that
the frequency of rs2056899A/T and rs10789501T/C of
CYP4A22 was lower than public database. Our findings
suggest a possible association between the haplotype CGC of
CYP4A22 and hemorrhagic stroke. These results need further
studies based on larger cohort group with stroke, and its
functional study for the activity of haplotype CGC. This work
was supported by the Second stage of Brain Korea 21 project
in 2009.
135 OLIGONUCLEOTIDE ARRAY FOR DETECTING
LONG TANDEM REPEATS IN THE HUMAN GENOME
L. Yu* (1), H. Bruce (1), G. Benson (2), R. Bannen (3), P.
Warburton (4), T. Richmond (3), L. DeLisi (5), R. Margolis
(1)
1. Department of Psychiatry, Johns Hopkins University School
of Medicine 2. Departments of Biology and Computer
Science,Program in Bioinformatics,Boston University 3.
Reseach Informatics ar NimbleGen Systems Inc. 4.
Department of Genetics and Genomic Sciences,Mount Sinai
School of Medicine 5. Department of Psychiatry, New York
University
* lyu17@jhmi.edu
At least 12% of the human genome is subject to variations in
copy number. The scope of variation ranges from single bp
insertions and deletions to duplications and deletions of whole
chromosomes. Our emphasis here is on tandem repeats. Short
tandem repeats with repeating units of about 2-12 bp in length
have emerged both as powerful markers for linkage studies
and as mutations causing a number of human diseases. We
hypothesize that polymorphisms of longer tandem repeats
(unit length of 50 bp to >150,000 bp), relatively unexplored
features of the human genome, may also contribute to normal
human variation and to disease, including schizophrenia. To
systematically address this issue, we developed an
oligonucleotide array specifically designed to detect changes
in repeating units in 2977 tandem repeats with a mean length
of 4143 bp, using the Roche Nimblegen singleplex
Comparative Genomic Hybridization (CGH) oligonucleotide
platform. Validation by PCR confirmed the capacity of this
array to detect repeat length variation. We now report the
development of a second generation array, using the Roche
Nimblegen 12X135K platform, designed to increase the
number of repeats assessed and improve hybridization
efficiency. This new array examines 4064 repeats with units a
minimum of 50 bp in length and of at least 95% identity.
Once validated, this array will provide a new tool for the
discovery of genetic factors contributing to the etiology of
schizophrenia and other complex diseases.

HIGH THROUGHOUT SEQUENCING
136 454 BASED SEQUENCING ANALYSIS OF THE
DISC1 PATHWAY IN SCHIZOPHRENIA PATIENTS
L. Moens (1,2), P. De Rijk (1,2), K. Norrback (3), D.
Goossens (1,2), R. Adolfsson (3), J. Del-Favero* (1,2)
1. 1Applied Molecular Genomics Group, VIB Department of
Molecular Genetics, Belgium 2. University of Antwerp (UA),
Antwerpen, Belgium 3. Department of Clinical Sciences,
Division of Psychiatry, University of Umeå, Sweden
* jurgen.delfavero@molgen.vib-ua.be
Schizophrenia(SZ) is among the most common disabling brain
diseases worldwide, and its predisposition is influenced by a
complex interplay between genetic and environmental factors.
Despite major efforts during the last decade to identify risk
genes for SZ, only a handful of candidate genes could be
replicated in independent studies, and even a smaller number
demonstrated a clear biological support. A recent and
promising exception is Disrupted in Schizophrenia 1 (DISC1),
originally identified via a balanced chromosomal translocation
in a Scottish pedigree. Since then, compelling genetic and
functional evidence has been accumulating, and several
DISC1 interactors have been identified as independent genetic
susceptibility factors for psychiatric illness, indicating that
a‘DISC1 pathway’ is involved in the etiology of psychiatric
diseases. To investigate the involvement of the ‘DISC1
pathway’ in the etiology of SZ, we conducted an extensive
sequence analysis of DISC1and 10 known interaction partners.
Hereto, we applied a multiplex PCR based targeted pooled
sample sequencing strategy, using the 454 platform. 4 DNA
pools were sequenced (2 patient pools and 2 control pools),
each consisting of 40 DNA samples. Variant detection and
annotation was done using an in-house developed software
program designed to handle 454 data in pooled samples.
Obtained variants were verified and their frequency
determined by MassArray based genotyping. Although no
obvious difference in (rare) variation load between
schizophrenia patients and control individuals was observed,
we did identify some rare potentially etiological variants.
Furthermore, our results show that sequencing of pooled
samples is a valuable strategy for simultaneous rare variant
discovery and frequency estimation.
MOOD DISORDERS
137 ASSOCIATION OF MANIA AND
HYPOTHYROIDISM
D. Khemka* (1), J. Ali (1)
1. University Of Mississippi Medical Center
* dkhemka@psychiatry.umsmed.edu
In the differential diagnosis of mood disorders thyroid
abnormalities rank high on the list of medical conditions to be
ruled out in clinical practice. The classic associations are
bipolar disorder with hyperthyroidism and depression with
hypothyroidism. Recently we encountered two patients who
presented with mania in the presence of persisting
hypothyroidism. This prompted us to conduct a literature
review using Pub Med and Medline on a possible association.
Nine case reports were identified in the period from 1980
-2007. Analyses of these show the following associations:
1) Mania and hypothyroidism were reported mostly in
females; there is only one case report of a male with
hypothyroidism and co-occurring mania; 2) Rapid cycling and
hypothyroidism were reported more in females (consistent
with established data); 3) Treatment generally involved using
thyroid replacement (usually Levothyroxine).
No specific mechanism(s) underlying the association of
thyroid dysfunction and bipolar disorder were clearly
identified. In addition, no data is available on ethnic and
cultural variation. Further investigations to better understand
this association both from an etiological and therapeutic
perspectives are needed.

138 COMMON VARIANTS IN THE B3 NICOTINIC
RECEPTOR ARE ASSOCIATED WITH BIPOLAR
DISORDER, SCHIZOPHRENIA, AND NICOTINE
DEPENDENCE
S. Hartz* (1), P. Lin (2), N. Rochberg (1), S. Saccone (1), W.
Berrettini (3), H. Edenberg (4), E. Nelson (1), J. Nurnberger
(4), L. Bierut (1), J. Rice (1)
1. Department of Psychiatry, Washington University 2.
Biology & Biomedical Sciences, Washington University 3.
Department of Psychiatry, University of Pennsylvania 4.
Department of Psychiatry, Indiana University School of
Medicine
* hartzs@wustl.edu
Objective: Based on published associations between nicotine
dependence and nicotinic receptor subunits, we investigated
the association of schizophrenia and bipolar disorder with
nicotinic receptor subunits. Method: Our primary sample
consisted of 916 European American (EA) cases with bipolar
disorder, and 1028 EA controls. Based on known associations
with nicotine dependence, we genotyped 8 SNPs on
chromosome 8 (3 bins) in the regions of CHRNB3 and
CHRNA6, and 6 SNPs on chromosome 15 (3 bins) in the
regions of CHRNA5 and CHRNA3. Two African American
(AA) samples were used for validation: 389 subjects with
bipolar disorder and 671 controls, and 921 subjects with
schizophrenia and 941 controls. Results: Two highly
correlated synonymous SNPs in CHRNB3, rs4952 and rs4953,
were significantly associated with bipolar disorder (OR 1.74,
95% CI (1.2, 2.4), p=0.001). This association remained
significant both after adjusting for a smoking covariate and
analyzing the association in non-smokers only. Two SNP bins
(tagged by rs13439479 and rs7824160, r2=0.4 between the
two bins in Africans) in high LD (r2=1) with rs4952 in EA
were imputed in AA for both the bipolar and schizophrenia
samples. The association with bipolar disorder was validated
with rs13439479 (OR 1.78, p=0.007). An association with
schizophrenia was found with rs7824160 (OR 1.26, p=0.046).
Conclusions: Our results suggest that the β3 nicotinic receptor
subunit is associated with schizophrenia and bipolar disorder
in addition to its known association with nicotine dependence.
139 PREVALENCE OF DEPRESSION AND SOME
RELATED FACTORS AMONG DIABETIC PATIENTS
AT PHC/ DUBAI-UAE
H. Hussain* (1), Z. Kerem (1)
1. Dubai Department of Health and Medical Services
*hyHussain@dha.gov.ae
Recognition of depression may be troublesome among patients
with diabetes due to the overlap of symptoms, Co morbid
diabetes and depression may result in poor clinical outcomes,
impaired health status, economic burden, increased health care
utilization, and poor self-care behaviors .Objective: To study
the prevalence rate of depression among adults with diabetes
attending Jabal Ali Health center & assess some associated
factors. Materials & Methods: A cross sectional study has
been carried out to identify the prevalence of Depression
among DM patients, Systematic Random sample has been
used for this study, no of patients selected for the study was
114 out of total no of diabetic patients in JAC (341), Interview
questionnaire using Patient health questionnaire ((PHQ9)) was
used from the period 5th November 2007 – 3d march 2008 in
Dubai/UAE. Results: (12) patients found to have depression
out of total sample (114) examined, with a prevalence rate of
(11%), all case were mild to moderate depression with score
ranging from (5-14/27), all cases were middle age group
persons Age (20 – 55) years old, depression was significantly
associated with glycemic control factor, the mean of glycemic
control (HbA1C > .8.8%) among depressed in comparison
with non depressed patient (HbA1C .7%) P

140 CYTOCHROME P450 CYP1A2, CYP2C9, CYP2C19
AND CYP2D6 GENESARE NOT ASSOCIATED WITH
RESPONSE AND REMISSION IN A SAMPLE OF
DEPRESSIVE PATIENTS
R. Calati* (1), I. Massat (2), S. Linotte (2), S. Kasper (3), Y.
Lecrubier (4), R. Sens-Espel (5), J. Bollen (6), J. Zohar (7), J.
Berlo (5), P. Lienard (5), D. De Ronchi (8), J. Mendlewicz (2),
D. Souery (9), A. Serretti (1)
1. Institute of Psychiatry, University of Bologna, Bologna,
Italy 2. Université Libre de Bruxelles, Brussels, Belgium
3. Department of General Psychiatry, Medical University
Vienna, Austria 4. Hôpital la Salpetriere, INSERM U302,
Paris, France 5. DNA Vision sa, Charleroi, Belgium
6. Sint-Truiden, Psychiatric center, Sint-Truiden, Belgium
7. Chaim Sheba Medical Center, Tel-Hashomer, Israel
8. Institute of Psychiatry, University of Bologna, Bologna,
Italy 9. Laboratoire de Psychologie Médicale, Université Libre
de Bruxelles and Psy Pluriel, Centre Européen de Psychologie
Médicale, Brussels, Belgium
* raffaella.calati@unibo.it
Cytochrome P450 genes are involved in the oxidative
metabolism of antidepressants and have been hypothesized to
be implicated in treatment response. The aim of the present
study was to investigate the role of the allelic variations of the
cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and
CYP2D6 genes in antidepressant treatment response and
remission rates. Two hundred and seventy-eight patients
(mean age: 58.77±14.67 years; female/male: 206/72) affected
by major depression, responders (N=81) and non-responders
(N=197) to at least one adequate antidepressant treatment,
were recruited with a multicenter design for resistant
depression and genotyped for all relevant variations.
Genotypes were also pooled in activity profiles according to
the literature (as an example, for the CYP2D6 gene profiles
were poor, intermediate, extensive, and ultra-rapid). Using the
General Linear Model and covariating for age and gender, the
metabolic profiles of the genes were not associated with
response and remission in the whole sample. However
metabolic profile of antidepressants differ, therefore, we
repeated the analysis including as covariant the classes of
antidepressant with evidence of being metabolized by each
specific cytochrome but no association was found as well. The
investigated cytochrome genes do not seem to play a major
role in antidepressant response in the present sample of
depressive patients. Nevertheless, methodological and sample
size limitations of this study do not allow to provide definitive
conclusions.
141 HERITABILITY OF BIG FIVE PERSONALITY
FACTORS IN MULTIPLEX FAMILIES WITH
BIPOLAR DISORDER
E. Hare* (1), J. Contreras (2), H. Raventos (2), R. Mendoza
(3), D. Flores (4), A. Jerez (4), H. Nicolini (5), A. Ontiveros
(6)
1. University of Texas Health Science Center, San Antonio
2. School of Biology and Center for Cellular and Molecular
Biological Studies, University of Costa Rica 3. LABIOMED,
UCLA 4. Centro Internacional de Trastornos Afectivos y
Comportamiento Adictivo (CITACA),Guatemala City
5. Grupo de Estudios Medicos y Familiares Carracci,
S.C.,Mexico City 6. INFOSAME,Monterrey, Mexico.
* hare@uthscsa.edu
Associations have been observed between bipolar disorder and
personality traits such as openness to experience and
extraversion. In this study, 136 families including 351
individuals with bipolar disorder I and their family members
(1148 total subjects) took the short form of the NEO-PI-R.
Best-estimate diagnosis of bipolar I was made using the
Diagnostic Interview for Genetic Studies, Family Interview
for Genetic Studies, and the patients' medical records.
Heritabilities were 0.28, 0.23, 0.24, 0.20, and 0.35 for
Agreeableness, Conscientiousness, Extroversion, Neuroticism,
and Openness to Experience, respectively. Genetic
correlations between Big Five factors ranged from -0.81 for
Conscientiousness and Neuroticism to 0.77 for
Conscientiousness and Extraversion. The genetic correlation
between affectation with bipolar I and Extraversion was -0.32,
suggesting that common genetic factors affect the
development of bipolar I and introverted personality. Future
linkage and association analyses in this population are likely
to locate genomic regions associated with these traits,
ultimately leading to the identification of genes and
biochemical pathways involved in the development of bipolar
disorder and introverted personality.

142 CNV-DISCOVERY IN LINKAGE REGIONS FOR
BIPOLAR AFFECTIVE DISORDER
M. Lekman* (1), R. Karlsson (2), L. Graae (2), A. Carmine
Belin (2), D. Galter (2), I. Kockum (1), S. Paddock (2)
1. Dept. of Clinical Neuroscience 2. Dept. of Neuroscience
* magnus.lekman@ki.se
The aim of the present study was to analyze whether linkage
regions may harbor copy number variants with high
penetrance for the susceptibility of bipolar affective disorder
(BPAD). We carried out a combined whole-genome SNP and
CNV-analysis to correlate linkage scores with CNV contents.
Families were selected from 648 pedigrees (NIMH waves
I-IV) based on genome-wide parametric linkage analysis using
microsatellites. 277 individuals from 48 families were
included in our study and genotyped on the Human610-Quad
BeadChip-platform. Quality-control was performed to remove
poorly performing SNPs or SNPs located in regions of CNVs
(for calculating linkage scores). Only markers in linkage
equilibrium were included in the linkage analysis. CNV
detection was carried out using all 620,000 markers. Samples
with a standard deviation for the LogR ratio of more than 0.3
were re-genotyped. For the final analysis, all samples had a
standard deviation of the LogR-ratio less than 0.3. Our
preliminary CNV-discovery identified 12,935 CNVs
(PennCNV). Obvious cell-culture artifacts (e.g., trisomies)
were excluded from further analyses. Multipoint linkage
analysis (NPL-all) was performed under three different
affection status models (Merlin). Before weighted for CNVs,
maximum linkage regions were identified on chromosome 3p
(non-parametric LOD>2.75) and 18q (non-parametric
LOD>2.3), with several additional, lower peaks in other
regions. CNVs passing the calling-filter are currently
correlated with the sum of family-wise linkage scores and
further analyzed by functional studies regarding their possible
significance in BPAD susceptibility.
143 GENETIC OVERLAP BETWEEN BODY MASS
INDEX (BMI) AND RECURRENT DEPRESSION
M. Rivera* (1), S. Cohen-Woods (1), A. Schosser (1,2), K.
Aitchison (1), G. Breen (1), A. Butler (1), N. Craddock (3), M.
Gill (4), A. Korszun (5), C. Lewis (1,6), W. Maier (7), O.
Mors (8), M. Ng (1), M. Owen (3), K. Pirlo (1), M. Preisig (9),
J. Rice (10), M. Rietschel (11), R. Uher (1), I. Craig (1), A.
Farmer (1), P. McGuffin (1)
1. MRC SGDP Centre, Institute of Psychiatry, King's College
London. 2. Psychotherapy, Medical University Vienna,
Austria. 3. Department of Psychological Medicine, School of
Medicine, Cardiff University, Cardiff CF10 3XQ, UK. 4.
Department of Psychiatry, Trinity Centre for Health Sciences,
Dublin 8, Ireland. 5. Barts and The London, Queen Mary’s
School of Medicine and Dentistry, London E1 4NS, UK. 6.
Molecular Genetics, School of Medicine, King’s College
London. 7. Department of Psychiatry, University of Bonn,
53127 Bonn, Germany. 8. Department of Psychiatry,
University of Aarhus, DK-8000 Aarhus, Denmark. 9.
Department of Adult Psychiatry, University Hospital of
Lausanne, 1008 Prilly-Lausanne, Switzerland. 10. Department
of Psychiatry, Washington University, St Louis, MO 63130,
USA. 11. Central Institute of Mental Health, 68159
Mannheim, Germany.
* margarita.rivera_sanchez@kcl.ac.uk
There is growing evidence suggesting that rates of physical
disease, such as obesity, are much higher among people with
depression. Some recent studies support the hypothesis that
there may be shared aetiological factors between recurrent
unipolar depression, obesity and physical disorders. We aimed
to investigate genetic overlap between Body Mass Index
(BMI) and recurrent unipolar depression (UPD). The sample
consists of 2628 depression cases and 1023 controls
from several studies; Depression Case-Control (DeCC) study,
Bipolar Association Case-Control (BACC) study, Depression
Network (DeNT) study and the Genome Based Therapeutic
Drugs for Depression (GENDEP) study. The sample is part of
a genome-wide association study (GWAS) of unipolar
depression carried out by The Depression Consortium at the
SGDP Centre, Institute of Psychiatry. DSM-IV/ICD-10
depression phenotypes were ascertained using SCAN
interview. Controls individuals were screened for absence of
psychiatric disorder. Furthermore, a wealth of detailed data on
chronic, co-morbid physical diseases such as obesity, diabetes,
heart disease and migraine in both the cases and the controls
has been collected. These individuals were genotyped by CNG
(Paris) using Illumina 610 Quad array platform. We also
examined in detail known “obesity genes” FTO and MC4R in
depression cases and controls. Statistical analyses of
association between these SNPs and obesity and depression
was undertaken using PLINK.

144 LONGITUDINAL ASSOCIATIONS BETWEEN
ANXIETY SENSITIVITY, ANXIETY AND
DEPRESSION USING A GENETICALLY SENSITIVE
DESIGN
H. Zavos* (1), F. Rijsdijk (1), T. Eley (1)
1. Social, Genetic, & Developmental Psychiatry Centre,
Institute of Psychiatry, King’s College London
*helena.zavos@kcl.ac.uk
Anxiety and depression have a high incidence of co-morbidity
and are commonly occurring problems in childhood and
adolescence. Research has shown that the short variant of the
5HTTLPR reduces the transcriptional efficiency of the
serotonin transporter gene and is associated with both anxiety
and depression. Anxiety sensitivity, the fear of anxiety related
sensations, is a cognitive bias which has been associated with,
and is predictive of anxiety in childhood, adolescence and
adulthood. Previous research has also shown that anxiety
sensitivity is both phenotypically and genetically correlated
with depression. Our aim was to look at the relationships
between these variables developmentally to better understand
the direction of effects between them over the adolescent
period and given the high genetic correlation between
variables, look at associations between 5HTTLPR and a factor
score of the 3 variables. Longitudinal associations between
anxiety sensitivity, anxiety and depression were examined
using a genetic cross-lagged model. This model estimates
phenotypic causal effects of all variables on one another,
while controlling for concurrent (genetic and environmental)
associates between them. Analysis was conducted on 2-wave
sibling and twin data from the G1219 study (mean age 15
years at wave 1 and 17 years at wave 2). Genotyping of
5HTTLPR was performed of 1,467 individuals from the same
sample. Our data suggests that early depression leads to later
anxiety but that there is bi-directional relationship between
anxiety sensitivity and anxiety and depression. Effects of
genes were more stable over time whereas environmental
effects were more time specific.
145 NEW CANDIDATE GENES FOR BIPOLAR
DISORDER ARE REPLICATED IN SCANDINAVIAN
SAMPLES
M. Tesli* (1)
1. Institute of Psychiatry, University of Oslo, Department of
Psychiatry, Oslo University Hospital
*m.s.tesli@medisin.uio.no
Bipolar disorder (BD) has a complex and important genetic
component. Many genes, each with a limited effect, are
believed to interact with each other and with environmental
factors, to give rise to the disorder. Recent Genome-wide
association studies (GWAS) have found association between
variants of PALB2, ANK3 and BD. We wanted to replicate
these findings in Scandinavian samples. In a replication study
of PALB2 (n=787 cases/2862 controls), the preliminary
results showed a significant association with BD in our
Scandinavian sample (P=0.0058 after 100000 permutations).
This was followed by investigations of BRCA2, a gene which
function is closely related to that of PALB2, where the
preliminary results showed a significant association with BD
(P=0.0088 after Bonferroni correction). These findings
support PALB2 and BRCA2 as risk genes specifically for BD,
and suggest that dysfunctional DNA repair mechanism could
be involved in BD pathophysiology. The preliminary analysis
of ANK3 showed evidence of nominally significant
association between 14 of 111 ANK3 SNPs and BD in a
Norwegian case-control sample (n=182 cases/353 controls),
with a lowest nominal P-value of 0.003. Due to increasing
evidence of genetic overlap between BD and schizophrenia
(SCZ), we also genotyped these ANK3 SNPs in 230 SCZ
cases, and found 22 SNPs to be nominally significantly
associated with SCZ (lowest nominal P-value=0.0004). These
findings give further support to ANK3 being a BD
susceptibility gene and to the hypothesis of overlapping risk
genes between BD and SCZ.

146 COMT, INHIBITION, AND FUNCTIONAL
ABILITY IN MANIC BIPOLAR DISORDER
A. Minassian* (1), J. Kelsoe (1), M. Geyer (1), E. Twamley
(1), W. Perry (1)
1. U.C. San Diego Department of Psychiatry
*aminassian@ucsd.edu
Dysregulation of the dopaminergic (DA) system causes
impairments in the adaptive function of inhibition and is
thought to contribute to Bipolar Disorder (BD). The Valine
(Val) allele of the catechol-O-methyltransferase (COMT)
Val158Met polymorphism putatively reflects a genetic
propensity for DA underactivity in the frontal cortex and is
associated with the most profound inhibitory and daily
functioning deficits in schizophrenia patients. In BD,
however, little is known about whether a genetic
predisposition towards altered frontal DA activity may
influence the ability to complete daily activities. The presence
of inhibitory deficits may even mediate the relationship
between genes and functional ability. We obtained COMT
genotypes on acutely ill manic BD patients who were
administered the UCSD Performance-Based Skills Assessment
(UPSA-2), a role-play-based measure of functioning. Subjects
underwent testing in the human Behavioral Pattern Monitor
(hBPM), which quantifies exploratory activity. Val
homozygote manic BD patients had lower total UPSA scores
than did Methionine (Met) homozygotes, as well as trends
towards lower UPSA Comprehension/Planning and
Communication subscale scores. Moreover, worse UPSA-2
performance was associated with restricted, perseverative
exploration in the hBPM (r = -.87, p < .01). These preliminary
findings are consistent with our hypothesis that inhibitory
deficits such as perseverative behavior may influence the
relationship between genes and real-world functional ability.
The simultaneous study of genotypes and cognition might
yield a compelling model to explain variations in functional
ability in the BD population and identify the factors that make
these individuals most vulnerable to impairments in
day-to-day functioning.
147 DEPRESSION IS INFLUENCED BY MANY
COMMON GENETIC VARIANTS WITH SMALL
EFFECT PARTLY SHARED WITH ANXIETY
C. Middeldorp* (1), A. demirkan (2), N. Wray (3), P.
Sullivan (4), J. Hottenga (5), C. Janssens (2), B. Oostra (2), G.
Willemsen (5), E. de Geus (5), R. van Dyck (6), Y. Aulchenko
(2), W. Nolen (6), F. Zitman (7), D. Boomsma (5), B. Penninx
(8), C. van Duijn (2)
1. Biological Psychology, VU University Amsterdam, De
Bascule, Academic Center for Child and Adolescent
Psychiatry 2. Departments of Epidemiology and Clinical
Genetics, Erasmus University Medical Center Rotterdam 3.
Genetic Epidemiology, Queensland Institute of Medical
Research 4. Departments of Genetics and Psychiatry,
University of North Carolina 5. Biological Psychology, VU
University Amsterdam 6. Department of Psychiatry,
University Medical Center Groningen 7. Department of
Psychiatry, Leiden University Medical Center 8. Departments
of Psychiatry, VU University Medical Center Amsterdam,
University Medical Center Groningen, Leiden University
Medical Center
*cm.middeldorp@psy.vu.nl
Recently, with the use of Genome Wide Association Study
(GWAS) data, it has been shown that a substantial polygenic
component contributes to the risk for schizophrenia (ISC,
Nature, 2009). In addition, bipolar disorder appears to be
influenced by the same polygenic component. The genetic
architecture of depression and anxiety was investigated in a
similar way using genetic scores, based on GWAS results in
one set, to predict depression and anxiety in another set. The
Dutch discovery set consisted of 1738 subjects with
depression (MDD) and 1803 controls with over 400,000 SNPs
genotyped (Sullivan et al., Molecular Psychiatry, 2008). The
prediction set was another Dutch sample (ERF) consisting of
~1890 subjects who completed the Hospital Anxiety and
Depression Scale (HADS) and the Center for Epidemiological
Studies – Depression scale (CES-D) questionnaires. SNPs
were selected based on the p-values

148 COMMINGLING ANALYSIS OF THE
AGE-OF-ONSET IN BIPOLAR I DISORDER: TWO OR
THREE CURVE MIXTURE?
M. Grigoroiu-Serbanescu* (1), M. Rietschel (2), T. Paul (2),
T. Schulze (3), M. Noethen (4), S. Cichon (4), R. Elston (5)
1. Biometric Psychiatric Genetics Research Unit, Alexandru
Obregia Psychiatric Hospital, Bucharest, Romania 2. Dept.
Genetic Epidemiology in Psychiatry, Central Institute of
Mental Health, Mannheim, Germany 3. Unit on the Genetic
Basis of Mood and Anxiety Disorders, National Institute of
Mental Health, National Institutes of Health, US Department
of Health and Human Services, Bethesda, MD, USA 4.
Institute of Human Genetics and Dept. of Genomics, Life and
Brain Center, University of Bonn, Bonn, Germany 5. Dept.
Epidemiology and Biostatistics, Case WesternReserve
University School of Medicine, Cleveland, Ohio, USA
*maria.serbanescu@web.de
Age-of-onset (AO) seems to be a phenotypic variable with a
strong genetic component and therefore useful in molecular
analysis of bipolar disorder (BP). A debate about the cut-off
point for defining early AO has developed over the last few
years. Using an Expectation-Maximization algorithm Bellivier
et al (2001) found the best fit for a model with three
onset-groups, proposing the age 20-21 as cut-off for early
onset, while using finite mixture models Kennedy et al (2005)
found the best fit for a two onset-group model with age 40 as
cut-off and an incidence peak for mania in the age-band 21-25.
Based on segregation analysis, we proposed a two AO-group
model with cut-off age 25 for early onset
(Grigoroiu-Serbanescu et al. 2001). The present study aimed
at investigating the best AO-model in 468 Romanian BPI and
1458 German BPI patients using commingling analysis
(SAGEv6.01-software) (Elston et al, 2009). The best model
was selected according to Akaike’s A Information Criterion
(AIC). Results: The two and three AO-group models provided
similar AIC-values both in the Romanian and the German
sample. The means were 18 years (SD=7) in the Romanian
early-onset group (40% of cases) and 20 years (SD=9) in the
German early-onset group (50% of cases). Thus the cut-off for
early-onset (X + 1 SD) was different.Conclusion: Our results
overlapped with the findings of Kennedy et al (2005) showing
that two-curve and three-curve AO mixtures similarly fit the
AO-distribution in BPI disorder and the cut-offs for
early-onset differ by sample.
149 NON-PSYCHOTIC BIPOLAR I DISORDER
ASSOCIATED WITH G72 GENE IN A ROMANIAN
SAMPLE
M. Grigoroiu-Serbanescu* (1), C. Diaconu (2), S. Herms
(3), C. Bleotu (2), A. Neagu (2), R. Abou Jamra (3), M.
Noethen (3), S. Cichon (3)
1. Biometric Psychiatric Genetics Research Unit, Alexandru
Obregia Psychiatric Hospital, Bucharest, Romania 2. Stefan S
Nicolau Institute of Virology, Bucharest, Romania 3. Institute
of Human Genetics, Department of Genomics, Life and Brain
Center, University of Bonn, Germany
*maria.serbanescu@web.de
Objective: Since the complex G72/G30 was considered one of
the most replicated candidate gene for bipolar I disorder (BPI),
we investigated the association between this complex and BPI
in the Romanian population. Special attention was paid to the
association of G72/G30 with psychotic BPI in view of
previous contradictory results concerning this association
(positive findings: Schulze et al, 2005; Goes et al, 2007;
negative: Williams et al, 2006; Maheshwari et al, 2009).
Method: Fourteen G72-SNPs were genotyped at the Institute
of Human Genetics, Bonn in a Romanian sample of 198 BPI
patients and 180 controls screened for psychiatric disorders.
Statistical analysis was performed with FAMHAP and
Haploview v.3.32. The sample power to detect allelic
association was 84%. Results: All genotyped SNPs were in
HWE in controls and patients. The comparison of MAF in
patients and controls showed no association of the fourteen
SNPs with BPI in our total patient sample. But when
subdividing the sample according to the presence/absence of
psychosis (incongruent plus congruent) in at least one illness
episode, four SNPs reached nominal significance in the
non-psychotic BPI subgroup [rs3916965 (M12) (P=0.044),
rs1935057 (P=0.037), rs3916967 (M14) (P=0.043), rs2391191
(M15, non-synonymous) (P=0.043)]. In the same subgroup, a
two-SNP haploblock (GA) including M14 and M15 was
significantly associated with BPI (P=0.0524 for global ?2
corrected through permutations; OR=1.82).
Conclusion: Similarly to Williams et al. (2006) and Hattori et
al. (2003) we found the same G72-SNPs M12(G) and M15(A)
associated with non-psychotic BPI. No SNP was associated
with psychotic BPI.

150 DNA SEQUENCE ANALYSIS OF ERBB4 IN
BIPOLAR DISORDER WITH MOOD-INCONGRUENT
PSYCHOSIS
F. Goes* (1), S. Wheelan (2), J. Potash (1)
1. Dept. of Psychiatry, Johns Hopkins University School of
Medicine 2. Center for Computational Genomics, Johns
Hopkins School of Medicine
*fgoes@jhmi.edu
Introduction: Prior studies of bipolar disorder (BP) with
mood-incongruent psychosis (MICP) have shown that this
subphenotype is familial and possibly linked to chromosomal
regions implicated in susceptibility to schizophrenia. We
recently performed a secondary GWAS analysis of BP-MICP
in the Bipolar Genome Study (BiGS), where the strongest
association was found in ERBB4 (P = 1.15 x 10-6), a
neuregulin 1 receptor, also associated with schizophrenia. In
this study, we hypothesized that common and rare variants
might also be associated with BP-MICP, the form of BP with
arguably the greatest phenotypic overlap with schizophrenia.
Methods: Using the Sanger method, we have sequenced the
promoter region, all 28 exons, and splice sites of ERBB4 in
the 189 cases with BP-MICP from the BiGS study. Traces
were analyzed using Phred/Phrap for base calling and
sequence assembly, and bioinformatic annotation was
performed using a variety of publicly available tools.
Results: We identified 37 sequence variants, of which 17
were novel. Of these, four were in coding regions, including a
non-conservative missense mutation (Cys -> Trp) in exon 15.
Novel variants were also found in the UTRs (n=4) and in
splice site sequences (n=9). We are currently comparing the
burden of rare variants, both across the gene and within
annotated functional categories, with data from European
origin subjects of the 1000 Genomes Project. Conclusion: Our
ongoing analyses suggest that ERBB4, a putative
schizophrenia susceptibility gene, might harbor common and
rare variants associated with susceptibility to a form of bipolar
disorder with phenotypic similarities to schizophrenia.
151 GENETIC ASSOCIATION BETWEEN G PROTEIN
beta 3 SUBUNIT, INTERLEUKIN-10, TUMOR
NECROSIS FACTOR-alpha GENE POLYMORPHISMS
AND IRRITABLE BOWEL SYNDROME IN KOREANS
S. Lee (1), H. Lee (2), J. Choi (2), I. Sung* (1), H. Park (1),
C. Jin (1)
1. Konkuk University College of Medicine 2. Korea
University College of Medicine
*leehjeong@korea.ac.kr
The aim of this study was to determine the role of G protein
β3 subunit (GNB3), interleukin (IL)-10, and tumor necrosis
factor (TNF)-α gene polymorphisms in Korean patients with
irritable bowel syndrome (IBS) as diagnosed based on Rome
III criteria. Korean case and control subjects of the study were
recruited between December 2006 and December 2008 from
visitors to the Health Promotion Center and Digestive Disease
Center for gastrointestinal endoscopy. All the subjects signed
an informed consent for genetic analysis and completed
questionnaires on Rome III criteria and the Beck’s Depressive
Inventory. GNB3, IL-10, and TNF-α gene polymorphisms
were genotyped using a polymerase-chain-reaction-based
method. Multifactor dimensionality reduction (MDR) analysis
was used to assess gene-gene interactions. Although genotype
and allele frequencies for all polymorphisms did not differ
between the 94 IBS patients and 88 healthy controls, genotype
and allele frequencies of GNB3 showed marginal significance
between two group (X2=5.92, p=0.052; X2=3.76, p=0.053).
MDR analysis revealed that there were no significant
interactions of GNB3, IL-10, and TNF-α gene variants with
susceptibility to IBS (p > 0.05). According to the IBS
subtypes, GNB3 T allele was more strongly correlated with
IBS with constipation (12 of constipation-dominant type and
31 of mixed type) than with 51 diarrhea-dominant type and 88
normal subjects (X2 =13.91, P=0.008). The results suggest
that GNB3 825T allele frequency might be associated with
IBS with constipation in Koreans.

152 REPLICATION STUDY OF 3Q29 LINKAGE AND
ASSOCIATION FINDINGS IN BIPOLAR AFFECTIVE
DISORDER.
A. Schosser* (1), K. Fuchs (2), M. Stojanovic (2), M.
Schloegelhofer (3), S. Cohen-Woods (4), I. Craig (4), P.
McGuffin (4), H. Aschauer (3)
1. Dep. of Psychiatry and Psychotherapy, Medical University
Vienna, Austria; MRC SGDP Centre, Institute of Psychiatry,
King’s College London, UK 2. Dep. of Psychiatry and
Psychotherapy, Medical University Vienna, Austria;Center for
Brain Research, Div. of Biochemistry and Molecular Biology,
Medical University Vienna, Austria 3. Dep. of Psychiatry and
Psychotherapy, Medical University Vienna, Austria 4. MRC
SGDP Centre, Institute of Psychiatry, King’s College London,
London, UK
*alexandra.schosser@iop.kcl.ac.uk
We identified a bipolar disorder (BPD) susceptibility region
on chromosome 3q29 in a genome-wide linkage scan (Bailer
et al. 2002, NPL-score4.09 in BPD families and 2.19 in
schizophrenia families) and follow-up linkage analysis
(Schosser et al. 2004, NPL-scores >3 with five markers in
BPD families and 2.3 with one marker in schizophrenia
families) performed in Austria. These results were supported
by fine-mapping of 3q29 (Schosser et al.2007), finding
NPL-scores >3.9 with SNPs (single
nucleotidepolymorphisms) spanning a region of 3.46 Mbp in
BPD families, and >1.7 in schizophrenia families. These
results support the hypothesis of common genetic
contributions to both disorders. Since genetic association
studies are more powerful than linkage studies for detecting
susceptibility genes of small effect size, the aim of the current
study is to investigate the 3q29 region in a BPD case-control
sample (BACCS) from UK and replicate the linkage findings
from Austria.The BACCS sample consists of 522 cases
(DSM-IV, Diagnostic and Statistical Manual, 4 th Edition; and
ICD-10, International Classification of Diseases, 10thEdition)
and 512 controls. Cases were interviewed using SCAN
(Schedules forClinical Assessment in Neuropsychiatry) and
controls screened for a lifetime absence of psychiatric
disorders by a modified version of the Past History Schedule.
Genotyping of 96 SNPs in the identified 3q29 linkage region
is performed using the SNPlex Genotyping System (Applied
Biosystems, Foster City,CA, USA), and raw data are analysed
using the GeneMapper Software v3.7. The results of this
currently ongoing genetic association study will be presented.
153 FUNCTIONAL CONSEQUENCES OF THE ANK3
GENE POLYMORPHISM ON SUSTAINED
ATTENTION: INFLUENCES IN PATIENTS WITH
BIPOLAR DISORDER, THEIR FIRST DEGREE
RELATIVES AND HEALTHY CONTROLS.
G. Ruberto* (1,4), E. Vassos (2), C. Lewis (2,3), R. Tatarelli
(4), P. Girardi (4), D. Collier (2), S. Frangou (1)
1. Section of Neurobiology of Psychosis, Institute of
Psychiatry, King’s College London, UK 2. Social, Genetic &
Developmental Psychiatry Centre, Institute of Psychiatry,
King’s College London, UK 3. Division of Genetics and
Molecular Medicine, King’s College London School of
Medicine ,UK 4. Department of Psychiatry, Sant'Andrea
Hospital, Second Medical School, La Sapienza University,
Italy
*gaia.ruberto@kcl.ac.uk
Recent genome-wide genetic studies have reported a strong
association with Bipolar Disorder (BD) in a region
(rs10994336) within ANK3. Ankyrin 3, the protein coded by
this gene, is involved in facilitating the propagation of action
potentials by regulating the assembly of sodium gated ion
channels. Both these processes are crucially involved in
sequential signal detection which influences performance
during sustained attention tasks. Abnormalities in sustained
attention are prominent trait features of BD and may be
associated with genetic risk. We examined the relationship of
allelic variation in the ANK3 gene and sustained attention,
measured with the Degraded Symbol Continuous Performance
Test (DS-CPT) in sample (n=189) individuals comprising BD
patients (n=47), their unaffected first-degree relatives (n=75)
and healthy controls (n=67). We found that the risk allele T
was associated with reduced sensitivity and increased errors of
commission regardless of diagnosis. This genotype effect
appeared relatively specific to sustained attention and was not
present in the domains of general intellectual ability, memory,
decision making and response inhibition. Our results suggest
that the allelic variation in ANK3 impacts on sodium-channel
dependent cognitive processes relating to signal detection and
this mechanism may relate to risk for BD.

154 METAMOODICS: AN INTEGRATED WEB
RESOURCE FOR SYSTEMATIC META-ANALYSIS OF
GENETIC ASSOCIATION STUDIES IN MOOD
DISORDERS
M. Pirooznia* (1), F. Seifuddin (1), J. Judy (1), P. Belmonte
(1), J. Potash (1), P. Zandi (1)
1. The Johns Hopkins University School of Medicine
*mpirooz1@jhmi.edu
Nearly 15% of females and about 8% of males suffer from
mood disorders at some point in life. Recent advances from
the Human Genome Project and high-throughput technologies
like single nucleotide polymorphisms (SNPs) genotyping
platform have made it possible to study the complex genetic
architecture of mood disorders at an unprecedented scale.
However, these studies generate huge amounts of data and
their interpretation presents an imposing challenge. We have
developed a database with a web front application resource,
called Metamoodics, to integrate the existing data from
published genomic experiments of mood disorders. These
include data from three different classes of genomic
experiments: a) association studies of sequence variation, b)
association studies of copy number variation, and c) gene
expression studies. Data from these three classes of genomic
experiments are meta-analyzed and the synthesized results are
visualized within the context of relevant genomic annotations.
Metamoodics provides additional functionality for users to
conduct customized gene set enrichment analyses of the
meta-analyzed results in order to test various hypotheses about
the relevance of particular molecular pathways in the risk for
mood disorders. The first release of the database will include
data from three major depression genome-wide association
studies (GWAS), six bipolar disorder GWAS, over 500
candidate gene association studies, and sixteen genome-wide
expression studies. Metamoodics will act as a virtual hub
where the scientific community can explore the current state
of knowledge about which SNPs, genes, and pathways may
contribute to susceptibility to mood disorders. Current
developments in the project are available at
http://psychiatry.igm.jhmi.edu/metamoodics/.
155 GENOME-WIDE ASSOCIATION STUDY OF
PEDIATRIC DSM-IV BIPOLAR-1 DISORDER
E. Mick* (1)
1. Massachusetts General Hospital
*emick1@partners.org
We conducted a preliminary genome-wide association study
of pediatric Bipolar-I disorder (BP1) nested within an ADHD
GWAS of 735 affected-offspring trios genotyped on the
Illumina Human1M BeadChip. After applying quality control
filters association with pediatric BP1 was tested with 835,136
SNPs. ADHD children with psychiatric comorbidity were not
excluded from participation and 126 of trios had comorbid
BP1 disorder with an average age at onset of 7.3±4.8 years of
age. We observed one genome-wide statistically significant
association (p=2.7E-8), Bonferonnip-value=0.025) with a SNP
(rs2978024 MAF=0.24) located on chromosome 8q24.22 in
3rd intron of ST3GAL1 (ST3
beta-galactosidealpha-2,3-sialyltransferase 1). Two additional
SNPs in ST3GAL1 were statistically significant gene-wide
(rs2945787 at p=6.5E-6 and rs2978008 at p=7.0E-5) both also
located in the 3rd intron and in moderate LD with the
genome-wide significant finding (r2 = 0.6-0.78). ST3GAL1
encodes an enzyme that transfers sialic acid to
oligosaccharides; the resulting sialic acid rich glycoproteins
bind to the selectin family of cell adhesion molecules.
Although additional work is needed to replicate this finding is
noteworthy that ST3GAL1 has been associated with adult BP1
in two independent samples and is located under one of two
genome-wide significant linkage peaks from a meta-analysis
of 5,179 individuals (1,067 families) with adult BP-I disorder.

156 ANK3 SEQUENCING IN BIPOLAR DISORDER
CASES
A. McQuillin* (1), C. Her (1), K. Schlegel (2), A. Dedman
(1), S. Sharp (1), R. Kandaswamy (1), A. Anjorin (1), N. Bass
(1), J. Lawrence (1), H. Gurling (1)
1. University College London 2. University of Nottingham
*a.mcquillin@ucl.ac.uk
Collaborative genome-wide association analysis in 4,387 cases
of bipolar disorder and 6,209 controls found strong evidence
for association in a region encompassing the ANK3 (ankyrin
G) gene. Since then further evidence for association between
ANK3 and bipolar disorder has been reported. ANK3 is an
adaptor protein found at axon initial segments that has been
shown to regulate the assembly of voltage-gated sodium
channels. Sequence analysis of the ANK3 gene in bipolar
disorder cases has been performed to identify potentially
aetiological changes in the gene. Several novel potentially
functional changes have been detected in the gene. Full
genotyping of these potential aetiological changes will be
done in our sample of 1000 cases and 1000 controls.
157 GENOME-WIDE ASSOCIATION OF BIPOLAR
DISORDER
E. Smith* (1), J. Badner (2), T. Barrett (3), P. Belmonte (4),
W. Berrettini (5), C. Bloss (1), W. Byerley (6), W. Coryell (7),
D. Craig (8), H. Edenberg (9, 10), E. Eskin (11), T. Foroud
(10), E. Gershon (2), T. Greenwood (12), M. Hipolito (13), D.
Koller (14), W. Lawson (13), C. Liu (2), F. Lohoff (5), M.
McInnis (15), F. McMahon (14), M. Sarah (1), C. Nievergelt
(12), J. Nurnberger (14), E. Nwulia (13), J. Paschall (16), J.
Potash (4), J. Rice (17), T. Schulze (18), W. Scheftner (19), C.
Panganiban (20), N. Zaitlen (21), P. Zandi (4), P. Zhang (22),
S. Zollner (15), J. Kelsoe (12,23), N. Schork (1,24,25)
1. Scripps Translational Science Institute 2. Department of
Psychiatry, University of Chicago 3. Department of
Psychiatry, Portland VA Medical Center 4. Department of
Psychiatry, Johns Hopkins School of Medicine 5. Department
of Psychiatry, University of Pennsylvania 6. Department of
Psychiatry, University of California, San Francisco 7.
Department of Psychiatry, University of Iowa 8.
Neurogenomics Division, The Translational Genomics
Research Institute 9. Department of Biochemistry and
Molecular Biology, Indiana University School of Medicine
10. Department of Medical and Molecular Genetics, Indiana
University School of Medicine 11. Department of Computer
Science, University of California, Los Angeles 12.
Department of Psychiatry, University of California, San Diego
13. Department of Psychiatry, Howard University 14.
Department of Psychiatry, Indiana University School of
Medicine 15. Department of Psychiatry, University of
Michigan 16. National Center for Biotechnology Information,
National Library of Medicine, National Institutes of Health 17.
Division of Biostatistics, Washington University 18. Genetic
Basis of Mood and Anxiety Disorders Unit, National Institute
of Mental Health Intramural Research Program, National
Institutes of Health, US Dept of Health and Human Services
19. Department of Psychiatry, Rush University 20.
Neurogenomics Division, The Translational Genomics
Research Institute 21. Department of Computer Science,
University of California, Los Angeles 22. Biostatistics
Department, University of Michigan 23. Department of
Psychiatry, VA San Diego Healthcare System 24. Department
of Molecular and Experimental Medicine, The Scripps
Research Institute 25. Scripps Health
*ensmith@scripps.edu
To identify BD genetic susceptibility factors, we have
conducted genome-wide association in two populations: one
of European Ancestry (EA, n = 2,200 cases; n = 1,436
genotyped controls) and one of African Ancestry (AA; n =
345 cases; n = 670 controls). We have previously reported
results for a subset of these individuals that were genotyped
through the GAIN initiative. Here we expand the study with
an additional 1,199 EA cases and 403 EA controls genotyped
on the Affymetrix 6.0 chip. In the full EA dataset, the
strongest association did not reach genome-wide significance
(rs17498753 in C2orf34, P = 2 x 10-6), and previously
characterized associations at ANK3 and CACNA1C did not

significantly replicate, although the GAIN subset had shown
replication of rs1938526 in ANK3 (p = 0.036). This is
consistent with a marked heterogeneity in the genetic basis of
BD. We have partitioned this heterogeneity through more
precise characterization of clinical subphenotypes and by
performing analyses designed to detect alternative genetic
architectures. Preliminary analyses include an examination of
polygenetic effects from additive and epistatic models; rare
variants using population based identity-by-descent mapping;
and allelic heterogeneity using haplotype analyses.
Identity-by-descent mapping in the GAIN sample has yielded
loci with intriguing candidates including the locus around the
neuronal calcium sensor FREQ on chromosome 9 (P = 1 x
10-6), which will be further followed up in the full dataset.
These results suggest that although common variants may be
challenging to reproducibly identify in BD, alternative
analysis methods may be fruitful in identifying genetic factors
for BD.
158 MAPPING LOCI AND GENES FOR BIPOLAR
AFFECTIVE DISORDER IN 34 CONSANGUINEOUS
FAMILIES FROM IRAN USING SNP MICROARRAYS
N. Moghimi (1), A. Noor (1), A. Lionel (2), A. Ziaolhagh (3),
M. Ghadiri (3), M. Ohadi (4), J. Vincent* (1)
1. CAMH 2. The Hospital for Sick Children 3. Iran University
of Medical Sciences 4. The Social Welfare and Rehabilitation
Sciences University,Tehran
*john_vincent@camh.net
Homozygosity mapping is a powerful method for finding rare
recessive disease genes in monogenic disorders and may also
be useful for locating risk genes in complex disorders. We
have used Affymetrix 5.0 Single Nucleotide Polymorphism
micorarrays to screen 72 individuals from 34 consanguineous
families from Iran that are multiplex for bipolar affective
disorder (BPAD), genome-wide for homozygosity-by-descent
(HBD), or autozygosity, under the hypothesis that, in some
rare instances, there are autosomal recessive mutations that are
major risk factors for disease, and that autozygosity mapping
of consanguineous multiplex BPAD families will enable the
mapping of such genes. In addition, we looked for the
presence of copy number variants (CNVs) that may also be
risk factors for BPAD in these families. We identified 43 large
HBD regions. For instance, in one family with 4 affected
individuals we identified a 56Mb common HBD region on
chromosome 8 (including candidate genes such as IMPA1,
IMPAD1), and a 10Mb region on chromosome 17 (including
SLC6A4). In a second family with four affected sisters, we
identified a 7Mb HBD region on 5q35.2-q35.3, including the
genes DRD1 and GRM6. We plan to screen selected candidate
genes within these regions for homozygous mutations. We
have also identified a number of large runs of homozygosity
that appear frequently among the BPAD probands, including a
400Kb run that spans the glutamate receptor gene, GRIK6. We
also have found 48 CNVs of interest that potentially disrupt
candidate genes such as SYN3, SLC39A11, and S100A10.

159 EVIDENCE FOR MOLECULAR PATHWAYS IN
BIPOLAR DISORDER USING INDEPENDENT
GENOME-WIDE ASSOCIATION DATASETS
C. O'Dushlaine* (1), D. Ruderfer (1), S. Purcell (1), P. Sklar
(1)
1. MGH
*odushlaine@chgr.mgh.harvard.edu
The etiology of biopolar disorder (BP), particularly with
regards to enrichment of genetic association within specific
molecular pathways, remains poorly described. Here we apply
a recently described pathway analysis method to 325,690
SNPs common to two independent BP datasets (1,829 cases,
2,935 controls (WTCCC); 1,498 cases, 954 controls (Sklar et
al.)) and report pathways that are significantly enriched in
both. Among those pathways implicated in BP
pathophysiology were pathways relating to Glycan structures
and cell-adhesion molecules. Compelling evidence exists in
the literature supporting the putative effects of disturbance to
these pathways and processes in effecting the BP phenotype.
These pathways and their underlying genetic loci represent
new and promising targets for additional studies of BP.
160 INDEPENDENT EVIDENCE THAT REFINED
PHENOTYPING OF BIPOLAR PATIENTS REVEALS
SIGNIFICANT ASSOCIATION FOR GABAA
RECEPTOR GENES
R. Breuer* (1), M. Hamshere (2), J. Strohmaier (1), M.
Mattheisen (3), F. Degenhardt (4), S. Meier (1), T. Paul (1),
M. O’Donovan (2), T. Mühleisen (4), T. Schulze (5), M.
Nöthen (4), S. Cichon (4), N. Craddock (2), M. Rietschel (1)
1. Department of Genetic Epidemiology in Psychiatry, Central
Institute of Mental Health, University of Heidelberg,
Mannheim, Germany 2. Department of Psychological
Medicine, School of Medicine, Cardiff University, UK 3.
Institute for Medical Biometry, Informatics, and
Epidemiology (IMBIE), University of Bonn, Germany 4.
Institute of Human Genetics, Department of Genomics, Life &
Brain Center, University of Bonn, Germany 5. Unit on the
Genetic Basis of Mood and Anxiety Disorders, National
Institute of Mental Health, National Institutes of Health, US
Department of Health and Human Services, Bethesda, MD,
USA
*rene.breuer@zi-mannheim.de
There is increasing evidence that refinement of phenotype of
complex psychiatric disorders can produce stronger
association signals. Craddock et al.1 recently reported that the
index association signal obtained using a set of GABAA
receptor genes in bipolar disorder was enriched and became an
order of magnitude stronger in a much smaller subsample of
DSM IV bipolar patients who had been assigned a refined
RDC diagnosis of “schizoaffective disorder, bipolar (SABP).”
In order to replicate this finding, we re-diagnosed n=682 DSM
IV bipolar patients included in our previous GWA study
according to RDC criteria based on OPCRIT data
(RDC-SABP, n=352, and, RDC-nonSABP, n=330). We
applied a gene-based approach using all available SNPs
(n=362) in the 19 GABAA receptor genes. While no
association with a DSM IV diagnosis of bipolar disorder was
observed, significant association (p=8.8x10-3) was obtained
when only SABP patients were included. The genes making a
major contribution to these results were GABRB2
(p=1.9x10-4), GABRG2 (p=1.2x10-2) and GABRA1
(p=1.7x10-2). The strongest SNP association was obtained for
rs7714930 (p=1.1x10-5) within GABRB2. Our results thus
replicate the association findings for RDC-SABP with
GABAA receptor genes, and show that the refining of major
phenotypes may be a prerequisite to the identification of
genetic risk factors for complex psychiatric disorders.
1Craddock et.al. Mol Psychiatry, 2008 Jul 1. [Epub ahead of
print]

161 HIGHER LEVELS OF SUICIDAL BEHAVIOR ARE
ASSOCIATED WITH ELEVATED SCORES OF
NEUROTICISM AND SUBSTANCE USE IN A SAMPLE
OF BIPOLAR I AND BIPOLAR II SUBJECTS.
M. Kamali* (1), S. Langenecker (1), A. Prossin (1), A.
Vederman (1), M. McInnis (1)
1. University of Michigan, Department of Psychiatry and
Depression Center
*masoud@med.umich.edu
Introduction: Further differentiating the clinical phenotypes of
bipolar disorder will assist in the search for biomarkers.
Suicidal behavior is a common and dangerous complication of
bipolar disorder. Factors such as high impulsivity have been
associated with elevated risk of suicidal behavior. Higher
impulsivity has also been associated with substance use
disorder and violent and aggressive behavior. The subtype of
bipolar disorder with higher levels of impulsivity as indicated
by higher rates of aggression, suicidal behavior and substance
use could be categorized as a distinct phenotype and an
appropriate candidate for biomarker investigations. Methods:
The studied sample is part of the larger cohort of bipolar
subjects from the Heinz C. Prechter Longitudinal Project.
This is a longitudinal study of bipolar disorder with more than
400 subjects enrolled. Data from over 200 subjects with
bipolar I and II were used in this analysis. Information
regarding diagnosis, substance use and suicidal behavior was
collected using the Diagnostic Interview for Genetic Studies
(DIGS) and confirmed by a best estimate process involving at
least one of the authors. The NEO-PI personality inventory
was collected for all subjects. Results: The subjects with
higher levels of suicidal behavior showed elevated scores in
the N domain and N1-6 facets of the NEO-PI. Subjects with
higher rates of suicidal behavior also had higher levels of
substance use disorders compared to the non-suicidal bipolar
subjects. Conclusion: Higher scores on the six N facets of the
NEO-PI, which measure personality traits such as anxiety,
angry hostility, depression, self-consciousness, impulsivity
and vulnerability, along with substance use disorders are
correlated with higher rates of suicidal behavior in this
population of bipolar subjects. This phenotype of the disorder
may be a candidate for further biomarker studies.
162 A GENE EXPRESSION STUDY OF
SPERMIDINE/SPERMINE
N(1)-ACETYLTRANSFERASE (SSAT) IN BIPOLAR
PATIENTS CHARACTERIZED FOR THE RISK OF
SUICIDE: PRELIMINARY FINDINGS
A. Squassina* (1), D. Congiu (1), M. Manchia (1), P. Piccardi
(1), G. Severino (1), C. Chillotti (2), R. Ardau (2), M. Alda
(3), M. Del Zompo (1, 2)
1. Laboratory of Molecular Genetics, Department of
Neurosciences “B.B. Brodie”, University of Cagliari,
Monserrato, (Ca), Italy 2. Unit of Clinical Pharmacology of
the University Hospital of Cagliari, Italy 3. Department of
Psychiatry, Dalhousie University, Nova Scotia, Canada
*squassina@unica.it
It is well known that chronic lithium treatment significantly
reduces the risk of suicide in subjects with major affective
disorders. A number of studies reported an underexpression of
spermidine/spermine N(1)-acetyltransferase (SSAT) gene, a
key enzyme of the polyamine system, in several brain regions
of suicide victims (Sequeira et al. 2006; Guipponi et al.,
2008). Interestingly, some evidences shows that lithium in
vitro induces an upregulation in SSAT expression in
lymphoblasts from bipolar patients (BD). In this abstract we
present data of a preliminary study in which SSAT expression
was measured in a group of lymphoblastoid cell lines (LCL)
from 7 Sardinian BD subjects that were part of a sample of 29
BD patients characterized for the risk of suicide. LCLs from
each subject were divided into two lines: one was treated with
lithium 1mM for 1 week while the other was not treated. The
fold changes in SSAT relative expression levels were
calculated using the ΔΔCt method. The analysis of paired
SSAT expression values showed that lithium significantly
increases SSAT expression (fold difference = 1.20; paired t
test, p = 0.006). The limited number of LCLs included in this
preliminary study did not allow us to perform comparisons
among the groups of patients with different risk of suicide.
Our preliminary findings provide strong support for an
upregulating effect of lithium on SSAT expression in
lymphoblasts. Further analyses of the entire sample will
provide more insights into the role of SSAT in lithium
mechanism of action and in the risk of suicide.

163 A GENOME-WIDE ASSOCIATION STUDY OF
AMYGDALA ACTIVATION IN YOUTHS WITH AND
WITHOUT BIPOLAR DISORDER
X. Liu*, N. Akula, M. Skup, M. Brotman, E. Leibenluft, F.
Mcmahon
*liuxinmin@mail.nih.gov
OBJECTIVE: Functional magnetic resonance imaging (fMRI)
is commonly used to characterize brain activity that may
underlie a variety of psychiatric disorders. Previously, fMRI
uncovered differences, compared to healthy controls, in
amygdala activation during a face processing task in pediatric
patients with bipolar disorder. In order to explore the genetic
architecture of this neuroimaging phenotype, we undertook a
genome-wide association study. METHOD: 39 patients with
bipolar disorder and 29 healthy controls, who had previously
undergone fMRI when viewing a neutral face, were genotyped
with a genome-wide single nucleotide polymorphism (SNP)
array. After quality control, a total of 104,043 SNPs were
tested against normalized amygdala activation scores obtained
from the right and left hemispheres. Genetic association was
tested with covariates to control for race and ethnicity.
RESULTS: Right amygdala activation under the hostility
contrast was most strongly associated with a SNP in the gene
DOK5 (rs2023454, P=4.88x10-7, FDR=0.05), a substrate of
TrkB/C receptors that is involved in neurotrophin signaling.
This SNP accounted for about 32% of the variance among
youth with bipolar disorder and 12% of the variance among
healthy youth in this sample. Interesting results (FDR

165 A FAMILY BASED STUDY OF DENOVO COPY
NUMBER VARIANTS IN BIPOLAR DISORDER USING
A 2.1 MILLION PROBE MICROARRAY CGH
PLATFORM
D. Malhotra* (1), V. Makarov (1), S. McCarthy (1), A.
Malhotra (2), J. Potash (3), F. McMahon (4), T. Schulze (4),
E. Leibenluft (5)
1. 1 Bungtown Road, Cold Spring Harbor, New York 2.
Department of Psychiatry Research, The Zucker Hillside
Hospital, Glen Oaks, Long Island, New York 3. Department of
Psychiatry and Behavioral Sciences Johns Hopkins Hospital,
Baltimore, Maryland 4. Genetic Basis of Mood and Anxiety
Disorders Unit; Institute for Mental Health, National Institutes
of Health, Bethesda, Maryland 5. Genetic Basis of Mood and
Anxiety Disorders Unit; Institute for Mental Health, National
Institutes of Health, Bethesda, Maryland 6. Mood and Anxiety
Disorders Program, National Institute for Mental Health,
National Institutes of Health, Bethesda, Maryland
*malhotra@cshl.edu
The role of copy number variants in the etiology of bipolar
disorder has been much less studied. Recent studies show that
rare denovo CNVs occur with significantly increased
frequency in children with neurodevelopmental disorders like
autism and schizophrenia. However, the role of denovo cnvs
in patients with mood disorders, including bipolar disorder is
not known. To investigate the role of denovo cnvs in bipolar
disorder, we initiated a family based genetic study called
GEM (Genetics of early onset Mania) on 198 bipolar trios.
The GEM bipolar sample collection includes a significant
fraction of bipolar cases that are sporadic and also,
approximately half of patients in the collection have an early
age-at-onset (age at first mania

167 AKT1 AND NEUROCOGNITION IN BIPOLAR
DISORDER
C. Nnadi* (1), K. Burdick (1), C. Hodgkinson (2), B. Buzas
(2), P. DeRosse (1), T. Lencz (1), D. Goldman (2), A.
Malhotra (1)
1. Psychiatry Research, The Zucker Hillside Hospital, North
Shore-Long 2. Laboratory of Neurogenetics, National Institute
of Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
*cnnadi@lij.edu
Background: The AKT1, a gene encoding a serine/threonine
kinase, modulates gene expression, protein synthesis and cell
cycle apparatus and is involved in the pathways for
lithium-sensitive cell survival and proliferation. Recent data
appear to implicate a haplotype of AKT1 in susceptibility to
schizophrenia and in decreased AKT1 protein levels in the
brains of individuals with schizophrenia (Emamian et al
2004). Interestingly, a linkage study of bipolar disorder
reported a modest signal in chromosome 14q 22-32 in the
region of AKT1. Thus, in the current study, we tested for
association of AKT1 gene and bipolar diagnosis and also
analyzed our data for the role of AKT1 in neurocognition
Methodology/Principal findings: Following an informed
consent process, we recruited and characterized 206 unrelated
Non-Hispanic White participants. Participants with bipolar
disorder (n=81) had mean age 37.2 ± 12.3 years; female
49.9%. Study controls (n=125) had mean age 36.9 ± 14.1
years, female 46.4%. Diagnosis used the Structured Clinical
Interview for DSM-IV (SCID) version 2.0, clinical notes and a
consensus opinion of at least 3 experts. Each participant gave
30cc of whole blood for DNA extraction and to establish
immortalized cell lines. The three single nucleotide
polymorphisms (SNPs) from the Emamian haplotype, rs
22498799, rs 3730358 and rs1130214, were genotyped and
examined for association with bipolar disorder and
neurocognition.None of the three SNPs was associated with
bipolar disorder (all p-values >0.05). However, AKT1
rs2498799, that was previously associated with schizophrenia
risk (risk allele =G), significantly influenced cognitive
performance among the bipolar sample but not among the
control subjects. Specifically, bipolar patients who carry two
copies of the risk allele (G) performed significantly worse on
measures of pre-morbid IQ and working memory than did
A-allele carriers. Conclusions/Significance: We found no
association between AKT1 gene polymorphisms and bipolar
disorder in our cohort. However, AKT1 gene appears to be
associated with neurocognition in our sample of Caucasian
bipolar patients.
168 FUNCTIONAL ASSESSMENT OF S100B AS A
SUSCEPTIBILITY GENE FOR BIPOLAR DISORDER
E. Dagdan* (1), M. Hill (2), S. Roche (1, 3), P. McKeon (3,
4)
1. Smurfit Institute of Genetics, Trinity College, Dublin,
Ireland 2. Neuropsychiatric Genetics Research Group,
Institute of Molecular Medicine, Trinity Centre for Health
Sciences, St. James' Hospital, Dublin, Ireland 3. Department
of Psychiatry, Trinity College, Dublin, Ireland 4.St. Patrick's
Hospital, Dublin, Ireland
*elif.dagdan@yahoo.ie
Introduction: The glial cell-derived neurotrophic factor,
S100B, is implicated in the pathology of bipolar affective
disorder (BPAD) and schizophrenia. S100B protein levels are
elevated in serum of patients with both disorders and S100B
variants are associated with schizophrenia. We previously
reported association of a SNP in the promoter ofS100B,
rs3788266, with a psychotic form of BPAD (P=0.0088). The
disease-associated C allele disrupts a Trex/MEF3 consensus
recognition, which is bound by Six-family transcription
factors, suggesting that it could affectS100B expression.
Methods: The functional effect of rs3788266 onS100B
promoter activity was determined using the luciferase reporter
system. Promoter fragments containing the T or C alleles of
rs3788266 were subcloned into the pGL4.23 minimal
promoter-luciferase vector and were assayed for activity in
U373MG glioblastoma cells. S100B RNA and protein levels
were measured in post-mortem brain tissue and serum,
respectively, to test for possible genotypic effects in vivo. The
allelic expression imbalance (AEI) of rs3788266 was also
investigated in 41heterozygote post-mortem brain RNA
samples. Finally, allelic effects on protein complex formation
at theS100B promoter were investigated by an electrophoretic
mobility shift assay (EMSA). Results: Luciferase reporter
gene expression was significantly increased in the presence of
the T- compared to C-allele (t= 4.151, P=0.001). However,
lower mean serumS100B levels were observed in BPAD
individuals with the TT genotype compared to those with the
TC or CC genotypes (ANOVA: F=13.44, P=0.001). A similar
pattern was observed at the RNA level but was not significant.
The binding affinity of a U373MG protein complex that binds
to the S100B promoter was 40 % stronger on the T- compared
C-allele promoter fragments. Allelic expression imbalance
was not observed with rs3788266, but we are investigating
other variants. Discussion: The disease-associated C allele of
rs3788266 is associated with reduced promoter activity in
U373MG glial cells and increased protein levels in serum.
SNP rs3788266 may represent a functional susceptibility
variant that contributes to the increased S100B levels observed
in BPAD patients. We are investigating the effect of other
SNPs on S100B RNA and serum levels.

169 GENOME-WIDE ASSOCIATION OF
SELF-REPORTED CO-MORBID SEIZURES IN
INDIVIDUALS WITH BIPOLAR DISORDER
A. Schork* (1, 2), C. Bloss (2), E. Smith (2), J. Kelsoe (1), N.
Schork (2, 3)
1. UCSD 2. Scripps Translational Science Institute 3. The
Scripps Research Institute
*aschork@ucsd.edu
Individuals diagnosed with affective disorders exhibit a higher
prevalence of seizures than the general population. Further,
there is considerable overlap in drug treatments for both
conditions, with anti-convulsants often used to prevent mood
swings in individuals with bipolar disorder (BD). These
observations, together with evidence that both seizures and
BD are closely related to noradrenergic and serotonergic
pathways in the human brain, led us to conduct a
genome-wide association study (GWAS) of co-morbid
seizures in two samples of individuals with BD. Our initial test
of association was performed in a sample of 1,001 individuals
with BD (n=82 with co-morbid seizures) genotyped through
the Genetic Association Information Network (GAIN) Bipolar
Genetics Study (BiGS). This sample was then combined with
1,199 additional cases (n=93 with co-morbid seizures) from
the Translational Genetics subsample of BiGS. Standard
univariate association analyses were performed using PLINK.
The strongest statistical signal from the combined sample in
this BD case-only association analysis was found for a SNP
between PHF14 and THSD7A on chromosome 7 (4.01 x 10-9;
OR = 5.276), a region that has been previously implicated in
cerebellar ataxia. Secondary analyses have provided further
support for this association, although further replication is
needed, particularly in cohorts where the seizure phenotype
has been more rigorously defined. Overall, our findings
suggest that co-morbid seizures and BD may represent a more
homogenous form of neuropsychiatric illness, with identifiable
genetic underpinnings. It is possible that GWAS applied to
clinically homogenous sub-groups may have greater utility for
gene identification in complex disorders.
170 ASSOCIATION OF THE SEROTONIN
TRANSPORTER GENE (SLC6A4) POLYMORPHISMS
WITH COMMON MENTAL DISORDERS IN A
BRAZILIAN POPULATION COHORT
U. Paredes* (1, 2), M. Diniz (1, 2, 3), A. de Saloma (1, 2, 3),
X. Xu (1, 2), C. Guindallini (3), J. Mari (3), R.
Affonseca-Bressan (3), P. McKeigue (4), . Prince (2), C.
Lewis (2), G. Breen (1, 2)
1. SGDP 2. IoP King's college London 3. UNIFESP 4.
University of Edinburgh
*ursula.paredes@kcl.ac.uk
We present preliminary results from genetic study using a
unique Brazilian cohort (from Sao Paulo [SP] and Rio de
Janeiro [RJ]) to unveil the complex genetic and environmental
aetiology of Common Mental Disorders (CMDs). These states
were selected as it has been demonstrated previously that
SP&RJ are stressful environments with high violent crime and
inequality and that the populations are highly admixed. For
this purpose we collected DNA from a cohort of 2200 subjects
selected via a cross-sectional survey with a multistage
probability sample design used to draw a representative
sample in the cities of SP and RJ. The cohort was then
assessed with the Composite International Diagnostic
Interview version 2.1 and 9 other scales including the General
Health Questionaire, Social Capital scale, and the Risk and
Resilience Factor Questionnaire. We conducted a preliminary
analysis of the prevalence of serotonin transporter gene
(SLC6A4) promoter, intron 2 and Ile 425 polymorphisms as
variants of these markers has been previously shown to act as
a risk factors for a variety of CMDs e.g. depression, PTSD,
etc.

283 CLASSIFICATION OF BEHAVIORS DURING
MANIA: A NOVEL APPROACH TO BIPOLAR
GENETICS
R. McKinney* (1), T. Greenwood (1), J. Head (1), J. Cadigan
(1), B. Study (2), Bipolar Genome Study (BiGS), J. Kelsoe (1)
1. UCSD Dept of Psychiatry
* rmckinney@ucsd.edu
Although the high rate of heritability in bipolar disorder
(BPD) is well demonstrated, the search for specific
susceptibility genes has been challenging. It is likely these
mapping difficulties are in large part the result of a high level
of genetic and allelic heterogeneity. BPD may result from
genetic variants in a variety of different brain signaling
systems. Therefore, any clinical or other trait that could
distinguish these variants would be invaluable in reducing
heterogeneity. We describe a novel, strictly behavioral
approach based on impairing actions displayed during manic
and mixed states. Information was collected regarding these
behaviors using DIGS ratings from our bipolar GWAS study
(BiGS). Clinicians independently coded behaviors for 935
subjects to determine whether each of 22 behavioral categories
were present. Multiple correspondence analysis was used with
564 unrelated individuals to explore and reduce the
dimensionality of the data, with six dimensions explaining
roughly 39% of the variance. We then used SOLAR to assess
the heritability of both individual behaviors and the
dimensions in a set of 356 affected sibling groups. Of
individual behaviors, several displayed significance, including
compulsive (h2=0.85, p=2x10-6) and sexual (h2=0.89,
p=5x10-9) behaviors. In addition, we have taken a
preliminary look at genetic association as well as developed a
new self report questionnaire assessing manic behaviors.
These data support the concept that the types of behaviors
displayed during mania may be heritable and index different
forms of BPD. This approach may then be useful in
identifying susceptibility genes, underlying pathophysiology
and clinical applications.
284 BDNF MET-CARRIERS SHOW WHITE MATTER
ABNORMALITIES IN RECURRENT DEPRESSION
J. Cole* (1), C. Fu (1), A. Farmer (1), S. Cohen-Woods (1),
D. Gaysina (1), N. Craddock (2), J. Gray (1), C. Gunasinghe
(1), F. Hoda (1), L. Jones (3), J. Knight (1), A. Korszun (4),
M. Owen (2), A. Sterne (1), I. Craig (1), S. Williams (5), A.
Simmons (5), P. McGuffin (1)
1. MRC SGDP Centre, Institute of Psychiatry, King's College
London 2. Department of Psychological Medicine, Cardiff
University, School of Medicine 3. Division of Neuroscience,
Department of Psychiatry, University of Birmingham 4.
Centre for Psychiatry, Wolfson Institute of Preventive
Medicine, Barts and The London 5. Centre for Neuroimaging
Sciences, Institute of Psychiatry, King's College London
*james.cole@iop.kcl.ac.uk
Background: White matter abnormalities have previously been
reported in both young and elderly patients with major
depressive disorder (MDD), however little is known about
genetic influences on white matter in MDD. Brain derived
neurotrophic factor is known to play a role in neuronal
survival and differentiation and carrying the met allele of the
val66met SNP has been shown to confer greater number of
white matter hyperintensities in MDD.
Objective: To investigate whether a plausible risk genotype,
BNDF val66met, has an effect on white matter integrity in
depression, using diffusion-tensor imaging techniques.
Methods: Diffusion-weighted MR scans were obtained from
49 recurrent MDD patients (mean age = 50.1 yrs, 31 females,
18 males). These scans were then grouped by val66met
genotype (19 met carriers versus 30 val/val homozygotes) and
underwent a voxel-based group mapping analysis of fractional
anisotropy (FA). The two comparison groups were matched
for age, sex, IQ and current depression levels.
Results: Met-allele carriers have significantly decreased FA
scores in four large voxel clusters throughout the brain,
compared to val/val homozygotes. These clusters were located
in bilateral corona radiata regions and the corticospinal tract.
Conclusions: The study indicates that having at least one met
allele in codon 66 of the BDNF gene is associated with widely
distributed decreases in white matter microstructural integrity
in patients with major depressive disorder.

OTHER CHILDHOOD DISORDERS
171 READING DISABILITIES AND ADHD:
CANDIDATE GENES ON CHR.6
A. Elbert* (1), L. Gomez, T. Cate-Carter (2), K. Wigg, Y.
Feng, A. Pitch, A. Ickovicz, M. Malone, E. Kerr, M. Lovett
(2), C. Barr (3)
1. University of Toronto: Institute of Medical Sciences 2.
Sickkids Hospital 3. University of Toronto: Dept of Psychiatry
*adrienne.elbert@ymail.com
Reading Disabilities (RD) is the most common learning
disability, affecting 5-12% of children. ADHD is often
comorbid with RD and twin studies indicate common genetic
influences. Previous linkage studies have identified
chromosome 6p as a risk locus, and two genes in this region,
KIAA0319 and DCDC2, have been associated to RD in
multiple samples. In a prior study, we mapped the putative
regulatory elements of KIAA0319 and DCDC2 using ChIP on
chip. The purpose of the current study was to investigate
polymorphisms within these regulatory elements in order to
determine whether they contribute to risk for RD and ADHD.
Eight polymorphisms in the regulatory element of KIAA0319
were tested for association in a sample of 291 nuclear families
with RD-affected children. Of these polymorphisms, a
microsatellite ([GT]n repeat) in the 1st exon of KIAA0319
showed our most significant result for association to RD in
this gene (p=0.009). It is established that longer (GT)n alleles
can decrease gene transcription by forming z-DNA, however it
is unclear how the microsatellite in KIAA0319 may be
contributing to RD risk. We previously found no evidence for
association of DCDC2 markers to our RD sample. However,
we recently found that these markers in DCDC2 were
associated with measures of hyperactivity and inattention in
the RD and ADHD samples. Therefore, I investigated the only
polymorphism in the putative regulatory element of DCDC2
in our RD and ADHD samples. The results did not provide
significant evidence for association to ADHD (p=0.07) or RD
(p=0.89).
172 STUDY OF THE
CATECHOL-O-METHYL-TRANSFERASE (COMT)
GENE WITH HIGH AGGRESSION IN CHILDREN
Y. Hirata* (1), N. King (1), B. Nowrouzi (2), J. Beitchman
(2), J. Kennedy (1)
1. Neurogenetics Section, Centre for Addiction and Mental
Health, the Departments of Psychiatry, the University of
Toronto, Toronto, ON, Canada 2. Child Psychiatry Section,
Centre for Addiction and Mental Health, the Departments of
Psychiatry, the University of Toronto, Toronto, ON, Canada
*yuko_hirata@camh.net
Background: The etiology of Childhood Onset Aggression
(COA) is still poorly understood, but early COA can be
considered as a strong risk factor for adult delinquency or
criminal behaviour. The COMT gene has been suggested to be
associated with aggression, as well as other psychiatric
disturbances such as schizophrenia, depression, suicide, and
attention deficit/hyperactivity disorder (ADHD). Methods:
168 children participated, who were required to have scores
ator exceeding the 90th percentile on the aggression subscale
of the parent-reported Child Behavior Checklist and also on
the Teacher's Report Form. The subjects must have shown a
minimum two-year history of aggressive behaviour. Four
COMT markers were genotyped for cases and controls
matched for gender and ethnicity. The cases were also divided
into subgroups using the Callous-Unemotional (CU) scale, as
well as ADHD status. Results: The four SNPs defined one LD
block. The genotype analysis of rs6269 (Val158Met) showed
nominally significant association (p=0.025) and rs4818
showed a trend (p=0.091). Haplotype analyses showed no
significant association. High versus low CU score groups
showed nominally significant association with rs6269
(p=0.019) and a trend with rs4818 (p=0.086). ADHD groups
showed no significant results. Conclusions: This is the first
report to our knowledge evaluating COMT SNPs with the
phenotype of high aggression in children, and we found a
possible role for the Val158Met marker in COA. Given the
importance of COA in future behaviour problems, further
investigation of COMT in this disorder is warranted.

173 A NOVEL LOCUS FOR AUTOSOMAL RECESSIVE
NON-SYNDROMIC MENTAL RENTARDATION
(NSMR) MAPS TO 13Q12.3-Q13.2.
A. Noor* (1), A. Mir (2), A. Mikhailov (1), A. Fennell (1), M.
Ayub (3), J. Vincent (1)
1. CAMH 2. COMSATS Inst, Islamabad 3. St. Lukes
Hospital, UK
*abdul_noor@camh.net
Mental retardation (MR) is defined by an intelligence quotient
(IQ) of less than 70 associated with functional deficits in
adaptive behavior, and has a prevalence of 1–3% in the
population. Although non syndromal autosomal recessive
forms of MR (NS-ARMR) are believed to be relatively more
common, only five genes have been reported so far. The
objective of the present study was to identify a new locus\gene
for ARMR. We ascertained a consanguineous family affected
with non-syndromic autosomal recessive mental retardation.
The phenotype was present in 4 individuals from two branches
of the family. To map the chromosomal location of the
causative gene we undertook Affymetrix 5.0 gene chip SNP
analyses of all affected individuals and two unaffected
individuals, assuming that a founder mutation was
responsible. All affected individuals shared a 4.9 Mb
haplo-identical region of homozygosity located on
chromosome 13q12.3-q13.2, defined by SNP markers
rs9506126 and rs9598929. The physical location of the critical
region is 28,727 Mb to 33,621 Mb (UCSC, March 2006) and it
contains ~30 Refseq genes. We have identified several
candidate genes within this locus including UBL3,
KATNAL1, FRY, PDS5B and KIAA0774. Sequencing of
candidate genes to identify the causative mutation is in
process. In summary, we have mapped the chromosomal
location of a novel gene responsible for autosomal recessive
non-syndromic mental retardation.
174 FIRST GENOME-SCAN ON
NEUROPHYSIOLOGICAL ENDOPHENOTYPES
POINTS TO TRANS-REGULATION EFFECTS ON
SLC2A3 IN DYSLEXIC CHILDREN
D. Roeske* (1), K. Ludwig (2), N. Neuhoff (3), J. Becker (2),
J. Bartling (3), J. Bruder (3), F. Brockschmidt (2), A. Warnke
(4), H. Remschmidt (5), P. Hoffmann (6), M. Nöthen (6), G.
Schulte-Körne (3), B. Müller-Myhsok (1)
1. Max-Planck Institute of Psychiatry, Munich, Germany 2.
Department of Genomics, Life & Brain Center, University of
Bonn, Germany 3. Department of Child and Adolescent
Psychiatry, Psychosomatics and Psychotherapy,
Ludwig-Maximilians-University Munich, Germany 4.
Department of Child and Adolescent Psychiatry and
Psychotherapy, University of Würzburg, Germany 5.
Department of Child and Adolescent Psychiatry and
Psychotherapy, University of Marburg, Germany 6. Institute
of Human Genetics, University of Bonn, Germany
*darina@mpipsykl.mpg.de
We present the results of a genome-wide association study on
EEG-measurements in dyslexic children. In 200 dyslexic
children, genotypes of 300.000 SNPs were associated with
two mismatch negativity (MMN) phenotypes, an early and a
late MMN component which have been shown to be
endophenotypes for dyslexia. 19 top SNPs were taken into
replication in a second German sample of 186 dyslexic
children. Rs4234898 could be replicated in this sample, with a
genome-wide significant result in the combined sample. This
SNP is located in an intergenic region on chromosome 4. In a
public available database (Dixon 2007) rs4234898 is
significantly associated with gene expression levels of
SLC2A3 with lower expression levels being present in
individuals carrying the T-allele. We confirmed this
trans-regulational effect in a cell line experiment using
lymphoblastoid cell lines from dyslexic children. This is in
concordance to our association results where carriers of the
T-allele showed an attenuated MMN. SLC2A3 is the main
glucose transporter in neurons. Our findings suggest that an
attenuated MMN in dyslexic children might be due to reduced
glucose levels. This is strengthened by several studies where
hypoglycaemia has been linked to deficits in learning and
memory. We find no evidence for a trans-regulation of
rs4234898 on SLC2A3 in gene expression data from adults.
This suggests that the identified effect might be restricted to
human childhood when a higher glucose demand is needed,
e.g. for cell migration processes such as elongating of axons or
branching of synapses. Acknowledgements GSK, BMM,
MMN were funded by the EU in the Sixth Framework
Program, LifeScienceHealth, project title Dyslexia genes and
neurobiological pathways (Neurodys, 018696)

PERSONALITY AND TEMPERAMENT
175 TRUE HEALING ART OF ALZHEIMER'S
DISEASE BY HOLISTIC HOMOEOPATHY
D. Patel*
*dr_darshanapatel@hotmail.com
Homoeopathic theory: The highest ideal of cure is rapid,
gentle and permanent restoration of health, or removal and
annihilation of the disease in its whole extent, in the shortest,
most reliable, and harmless way, on easily comprehensible
principle. Homoeopathy offers reasonably positive treatment
not cure but control and relief. Timely Administered
homoeopathy medicines can prevent further progress of
disease. The homoeopathic remedies work by stimulating the
body's own healing power. Homoeopathy the holistic
approach believes in treating the patient who is diseased and
not merely diseased parts of the patients. Every person is
unique and dementia affects people differently no two people
will follow exactly the same course and the homoeopathy the
ultimate pathy in the world believes in individuality of the
person has been shown to have a positive impact on the
progress of the disease. Homoeopathy undertakes study of
Each Alzheimer's as separate entity. The study also involves
deep evaluation of the mind and emotions & after that a
suitable medicine, called as constitutional medicine is given.
The medication brings deeper level healing. It should be noted
that there is no single specific remedy for all the cases of
Alzheimer's. The exact treatment is determined only on
in-depth evaluation of individual case.
176 INFLUENCE OF HTR2A POLYMORPHISMS AND
PARENTAL REARING ON THE PERSONALITY
TRAITS IN HEALTHY JAPANESE
Y. Nakamura* (1), Y. Ito (1), B. Aleksic (1), I. Kushima (1),
N. Yasui-Furukori (2), T. Inada (3), Y. Ono (4), N. Ozaki (1)
1. Department of Psychiatry, Nagoya University Graduate
School of Medicine, Nagoya, Japan 2. Department of
Neuropsychiatry, Graduate School of Medicine, Hirosaki
University, Hirosaki, Japan 3. Seiwa Hospital, Institute of
Neuropsychiatry,Tokyo, Japan 4. Health Center, Keio
University, Tokyo, Japan
*y-nakamu@med.nagoya-u.ac.jp
Introduction: Serotonin plays a significant role in the
biological basis of human behavior, psychiatric diseases and
temperamental predisposition. Genetic factors and
environmental influences significantly contribute to the
determination of human personality traits. The main purpose
of this study was to examine an influence of HTR2A
polymorphisms and parental rearing on temperament in
healthy Japanese. Methods: The subjects were 1,254 Japanese
volunteers (male=597, female=657), and 3 SNPs (rs6311,
rs6313, rs643627) were selected for genotyping. Out of 1,254
subjects, 1,245 completed the 125 items of the Japanese short
version of the Temperament and Character Inventory, and 572
completed the Japanese version of the Parental Bonding
Instrument. Result: All SNPs were in Hardy-Weinberg
equilibrium. As for female subjects a significant association
(p=0.003) was observed between rs643627 and novelty
seeking (NS). On the other hand, maternal overprotection had
significant effect on the score of harm avoidance (HA) in male
subjects only (p=0.049). Conclusion: Our result indicated the
relationship between the HTR2A rs643627 polymorphism and
NS only in females. The interplay between HTR2A receptor
and sex hormone might be responsible for the differences in
temperament between males and females. The results of our
study indicated that that maternal overprotection has more
influence than genetic factors on HA in male subjects. We
speculate that in males, the effects of genetic polymorphisms
on personality traits might be nullified by parental rearing.

177 ASSOCIATION BETWEEN OXYTOCIN
RECEPTOR GENE (OXTR) AND AFFECTIVE
TEMPERAMENTS
Y. Kawamura* (1), X. Liu (2), T. Akiyama (3), T. Shimada
(1), T. Otowa (1), Y. Sakai (4), C. Kakiuchi (1), T. Umekage
(5), T. Sasaki (6)
1. Department of Neuropsychiatry, Graduate School of
Medicine, University of Tokyo 2. Department of Human
Genetics, Graduate School of Medicine, University of Tokyo
3. Department of Psychiatry, Kanto Medical Center NTT EC
4. Department of Psychiatry, Juntendo University School of
Medicine 5. Division for Environment, Health and Safety,
University of Tokyo 6. Office for Mental Health Support,
University of Tokyo
*yoshiya-tky@umin.ac.jp
Background: Oxytocin is known to be related to social
interaction, trust and affectivity. Affective temperaments are
traits based on Kraepelin’s typological definition of
‘‘fundamental states’’ of manic depressive illness. They can
be measured by the Temperament Evaluation of Memphis,
Pisa, Paris and San Diego-Autoquestionnaire version
(TEMPS-A), and it was confirmed that they had a good
enough long-term stability to be considered as
endophenotypes. The objective is to assess the association
between oxytocin receptor gene (OXTR) polymorphism and
affective temperaments. Methods: Firstly, fifteen OXTR tag
single nucleotide polymorphisms (SNPs) were genotyped
using TaqMan® or direct sequencing. Secondly, haplotype
block structure was determined by Haploview 4.1. Lastly, the
association between SNPs and affective temperaments
(depressive, cyclothymic, hyperthymic, irritable and anxious
temperaments) was assessed by quantitative trait association
analysis permuted 10,000 times, and the association between
haplotypes and the temperaments was assessed by
haplotype-based quantitative trait association analysis with
Bonferroni correction, using PLINK 1.06 for 493 Japanese as
screened to exclude those who had lifetime diagnoses of
schizophrenia and other psychotic disorders by the
Mini-International Neuropsychiatric Interview (MINI).
Results: Two haplotype blocks were identified on OXTR.
Depressive temperament was significantly associated with
SNP rs11131149, rs13316193 (empirical p < 0.05) and one
common haplotype CTGTGGG
(rs11131149/rs2243370/rs2243369/rs13316193/rs2254298/rs2
268493/rs2268491) (adjusted p < 0.01). Cyclothymic
temperament was significantly associated with rs2268495
(empirical p < 0.05). Irritable temperament was significantly
associated with rs2268495 (empirical p < 0.01) and rs1042778
(empirical p < 0.05). Conclusions: The findings suggest that
OXTR polymorphisms or its haplotype are associated with
affective temperaments.
178 POPULATION GENETIC ANALYSIS AND
ASSOCIATION STUDY OF THE
CHOLECYSTOKININ-B RECEPTOR GENE WITH
PERSONALITY TRAITS
P. Zoë* (1), J. Bradwejn (2), J. Kennedy (3), X. Xia (4), D.
Koszycki (5)
1. Institute of Mental Health Research, Royal Ottawa Mental
Health Centre, Ottawa, Canada 2. Department of Psychiatry,
University of Ottawa, Ottawa, Canada 3. Neurogenetics
Section, Clarke Division, Centre for Addiction and Mental
Health, University of Toronto, Toronto, Ontario, Canada 4.
Centre for Advanced Research in Environmental Genomics,
University of Ottawa, Ottawa, Canada. 5. University of
Ottawa, Institute of Mental Health Research, Royal Ottawa
Mental Health Centre, Ottawa, Canada
*zoe.prichard@rohcg.on.ca
A polymorphism in the cholecystokinin-receptor gene
(CCKBR) has been associated with panic disorder (PD). This
study attempted to associate the same polymorphism with
personality traits that are postulated to increase vulnerability
to PD. Healthy volunteers completed the Anxiety Sensitivity
Index (ASI) and the NEO-Personality Inventory-Revised
(NEO-PI-R). No association was observed between anxiety
sensitivity or any personality trait with alleles previously
implicated in PD. Unexpectedly, Population genetics analysis
revealed the Caucasian sample (n = 103) to be in
Hardy-Weinberg Disequilibrium (HWD) in a sex-specific
pattern. Although there were no significant differences in
allele frequencies between the sexes, significant differences in
genotype frequencies were observed between the sexes. The
sample was also found to deviate from predictions under the
neutral-equilibrium and stepwise mutation models of
molecular evolution. The same genotypes implicated in the
deviation from Hardy Weinberg Equilibrium (HWE) were also
found to be associated with scoring low for the personality
traits of Openness and Conscientiousness. Interestingly,
Openness and Conscientiousness are not personality traits
predicted to play a role in the etiology of PD. Although this
study failed to detect the predicted relationship between
polymorphism and personality traits, the results are interesting
because the findings offer preliminary evidence for selection
at the CCKBR gene. The method of conducting association
analysis by first partitioning genotypes according to departure
from HWE is novel, and is a possible method for
understanding the dynamics of a population subjected to
forces that affect assumptions of evolutionary neutrality.

179 CANDIDATE GENE STUDY OF SCHIZOTYPY IN
NONPSYCHOTIC RELATIVES IN 270 IRISH
HIGH-DENSITY SCHIZOPHRENIA FAMILIES
A. Fanous* (1), D. Thiselton (2), V. Vladimirov (2), R.
Amdur (1), F. O'Neill (3), D. Walsh (4), B. Riley (2), X. Chen
(2), K. Kendler (2)
1. Washington VA Medical Center 2. Virginia Commonwealth
University 3. Queen's University, Belfast 4. Health Research
Board, Dublin
*ahfanous@vcu.edu
Background: It has long been observed that the relatives of
schizophrenics, even if not psychotic themselves, have odd
personality traits. These have been termed schizotypy, which
may be an endophenotype. It may include magical thinking,
ideas of reference, odd speech and behavior, and social
isolation. Candidate gene studies of schizotypy have only
been published since 2004. Furthermore, all of these previous
studies have used population, rather than family-based
samples. Methods: In our previous work in the Irish Study of
High-Density Schizophrenia families (n=270 families and
1408 individuals), we have reported positive associations in
DTNBP1, COMT, RGS4, Akt1, TAAR6, SPEC2, PDZ-GEF2,
ACSL6, IL3, CSFR2B, MEGF10, and FBXL21. We
hypothesized that at least some of these genes would contain
SNPs that influence schizotypy in non-psychotic relatives in
this sample. We tested schizotypy as a quantitative trait using
122 SNPs in these genes, previously tested for association
with schizophrenia, using the UNPHASED package. The
schizotypy trait consisted of the sum of ratings on all of the
individual items of the DSM-III-R criteria for Schizotypal
Personality Disorder. Results: We observed 4 contiguous
SNPs in MEGF10 with P

181 RELATIONSHIP BETWEEN D2 and D4
DOPAMINE RECEPTOR POLYMORPHISMS, STRESS
AND THE PERSONALITY TRAITS OF
EXTRAVERSION AND PSYCHOTICISM IN SONS OF
ALCOHOLICS
T. Ozkaragoz* (1), E. Noble (1)
1. UCLA
*tulino@ucla.edu
The influence of both molecular genetic (D2 and D4 dopamine
receptor polymorphisms) and environmental factors (i.e.
stress) on the personality traits of Psychoticism, Extraversion
and Neuroticism as measured by the Jr. Eysenck Personality
Questionnaire was investigated. High scorers on the
Psychoticism scale are described as impulsive, unempathic,
aggressive and sensation-seeking. Participants were 49 12-17
year old sons of of either active or recovering alcoholic
parents. It was found that sons of alcoholics (SAs) with the
DRD2 A1+ allele (A1/A1 and A1/A2 genotypes) showed
higher Psychoticism and Extraversion scores than SAs with
the DRD2 A1- allele (A2/A2 genotype). There also was a
positive relationship between stress and Psychoticism.
Furthermore, an interaction between the D4 dopamine
receptor gene and stress was found. Specifically, the
Psychoticism scores of SAs with the DRD4 7R+ allele (7R/7R
and 7R/Non7R genotypes) were more strongly influenced by
stress than the scores of SAs' with the DRD4 7R- allele
(Non7R/Non7R genotype) on this scale. A negative
relationship between age and Neuroticism and a positive
relationship between stress and Neuroticism also was found.
The results of this study suggest that the A1+ allele of the D2
dopamine receptor gene influences the expression of
Psychoticism and Extraversion in adolescent sons of
alcoholics. In addition, both the 7R+ allele of the D4
dopamine receptor gene and level of stress also appear to
contribute to the expression of Psychoticism.

PHARMACOGENETICS
182 AMINE RESISTANCE" IN BRAIN REWARD
CIRCUITRY AS A FUNCTION OF DRD2 GENE
POLYMORPHISMS IN REWARD DEFICIENCY
SYNDROME (RDS): SYNAPTAMINE COMPLEX
VARIANT INDUCED "DOPAMINE SENSITIVITY"
AND ENHANCEMENT OF HAPPINESS
K. Blum* (1, 2, 3), E. Stice (4), B. Downs (2), R. Waite (2),
E. Braverman (3, 5), M. Kerner (3), M. Oscar-Berman (6)
1. Department of Physiology and Pharmacology, Wake Forest
Unversity; Winston-Salem, North Carolina 2. Department of
Nutrigenomics, LifeGen, Inc.; San Diego, California 3. PATH
Clinics, New York, New York 4. Oregon Research Institute;
Eugene, Oregon 5. Department of Neurological Surgery, Weill
Cornell College of Medicine; New York, N.Y. 6. Departments
of Psychiatry and Anatomy & Neurobiology, Boston
University School of Medicine; and Boston VA Healthcare
System, Boston, MA
*drd2gene@aol.com
Since the discovery of the double helix, brain function in
terms of both physiology and behavioral traits have resulted in
a plethora of studies linking these activities to
neurotransmitter functions having a genetic basis. The
mechanisms underlining gene expression and the potential
impairments due to polygenic inheritance -- and as such,
predisposition to addiction and self-destructive behaviors --
have been amply identified. Human genetic information
derived from these scientific explorations may have important
links to feelings of well-being and potentially phenomena
related to “happiness.” While non-genetic oriented biological
explorations of social and political research have addressed
the impact of social and institutional environments on human
attitudes and behaviors, there is a paucity of research
exploring gene-environmental influences on these parameters.
Moreover, traditional fields such as Psychology and Molecular
Biology are subject to inherent limitations that may be
resolved only through collaboration across disciplines. By
contrast, attempts to identify key "vector influences" that link
genes, the brain, and social behaviors to a so-called state of
"happiness" are important areas for developing a new science
of human nature. Two disciplines, one relating to
spirituality("Genospirtuality") and the other to Political
Science, are beginning to emerge as fruitful grounds for
identification of specific polymorphic gene associations and
may pave the way to advance this new science. We address
the age-old question of "Nature vs. Nurture" as it relates to the
question of happiness and to the larger question relating to
human nature as an emerging science. It is well established
that in both food addicted and obese individuals there
is "dopamine resistance” due to an association with the
DRD2gene A1 allele. We propose a course of action that will
impact globesity, i.e., that a positive effect on body
composition/body mass index (BMI) will increase not only
self-image but also wellness, including a state of happiness.
Further, we propose a genetic map of happiness. We provide
preliminary evidence that utilization of a customized DNA
directed nutraceutical, LG839 [SYNATAMINECOMPLEX
VARIANT], significantly increased happiness (p < 0.05) in
obese subjects. Synaptamine is a putative dopaminergic
agonist, and it also is being investigated by using fMRI to
measure food induced blunted response in reward circuitry
(e.g., dorsal striatum and orbitofrontal cortex) in DRD2 A1
allele humans. We cautiously suggest that long-term activation
of dopaminergic receptors (i.e., DRD2 receptors) will
proliferate D2 receptors leading to enhanced "dopamine
sensitivity" and an increased sense of happiness.
183 SMOKING CESSATION MOLECULAR GENETICS
G. Uhl* (1), J. Rose (2), T. Drgon (1), F. Behm (2), D.
Walther (1), C. Johnson (1), Q. Liu (1)
1. NIH 2. Duke University
*guhl@intra.nida.nih.gov
Twin data support substantial heritable contributions to
individual differences in ability to quit smoking. Genome wide
association approaches identify small chromosomal regions
that are reproducibly tagged by clusters of SNPs whose allele
frequencies distinguish successful vs unsuccessful quitters in
clinical trial, general practice and community quitter settings
in the US and UK. Genes identified by these
clustered, reproducibly-positive results include numbers of
cell adhesion related genes, genes implicated in indivdual
differences in memory, and "druggable" genes. Some markers
display stronger association with quitting in trials of
bupropion, some with nicotine replacement (NRT) but most
with both. Data from retrospective analysis provided a v1.0
"quit success" genetic score that has provided significant
prospective results. This v1.0 score prospectively provides a
significant interaction with FTND assessments of nicotine
dependence to predict dose-related responses in individual
differences in ability to quit smoking. Taken together, these
data support polygenic contributions to smoking cessation
success from a number of allelic variants, including those that
we have validated in v1.0 quit success genotype scores.

184 GENE REGULATION BY DRUGS USED TO
TREAT MOOD DISORDERS
X. Deng* (1), P. McHugh (1), K. Doudney (1), P. Joyce (2),
M. Kennedy (1)
1. Christchurch, New Zealand 2. Department of Psychological
Medicine, University of Otago, Christchurch, New Zealand
*sarah.deng@otago.ac.nz
Antidepressant (AD) and mood stabilizer drugs are the main
treatments for mood disorders including major depressive
disorder and bipolar disorder. Although widely used, the
mechanisms of action of these drugs are not well understood.
Our first attempts to establish a model cell culture system to
study these drugs involved exposure of RN46A cells for 14
days, with various drugs, followed by transfection with
luciferase reporter constructs, in order to monitor gene
expression effects.Of the 19 promoter constructs tested,
occasional significant differences in expression were noted
between drug-exposed and control cell cultures. However,
these proved not to be robust or reproducible despite
considerable care in experimental design and execution. One
outcome of this work, however, was the finding that 72 hours
exposure of cells with the AD paroxetine appeared to give
optimal expression differences, which was chosen for future
experiments. Our second approach was to use quantitative
PCR analysis of candidate genes after exposure of RN46A
cells to various drugs for 72 hours. Our most striking results to
date are: (1) a gene called sepiapterin reductase (SPR), which
encodes a key enzyme in neurotransmitter synthesis, is
massively (>1700-fold, p=0.001) and specifically up-regulated
by sodium valproate; (2) another gene in the same pathway
(QDPR) is also significantly up-regulated; (3) the serotonin
receptor 2A (HTR2A) is significantly down-regulated by
paroxetine and citalopram, the two selective serotonin
reuptake inhibitor antidepressants (p=.001 to .003); and (4) the
histone deacetylase HDAC2 gene is reduced significantly by
all of the drug treatments except sodium valproate.
185 INFLUENCE OF TAAR6 POLYMORPHISMS ON
RESPONSE TO ARIPIPRAZOLE
A. Serretti (1), C. Pae (2), A. Chiesa* (1), L. Mandelli (1), D.
De Ronchi (1)
1. Institute of of Psychiatry, University of Bologna 2. The
Catholic University of Korea College of Medicine, Bucheon,
Kyounggi-Do, Republic of Korea
*albertopnl@yahoo.it
Background: There is some evidence suggesting a role of
TAAR6 in schizophrenia. The aim of the present study is to
investigate possible influences of a panel of markers in
TAAR6 (rs8192625, rs4305745, rs4305746, rs6903874,
rs6937506) on clinical outcomes and side effects in a sample
of Korean schizophrenic aripiprazole treated patients.
Methods: Efficacy was assessed at baseline and weeks 1, 2, 4,
6, 8 using CGI-S, CGI-I, BPRS and SANS. Side effects were
evaluated through SAS, BAS and AIMS. Multivariate analysis
of covariance (MANCOVA) was used to test possible
influences of single SNPs on clinical and safety scores. Tests
for associations using multi-marker haplotypes were
performed using the statistics environment “R”. Results: A
significant time per genotype interaction was found between
rs4305746 and repeated measures of ANOVA on BPRS scores
(F=2.45, d.f.=10,365, p=0.008). In particular G/A and A/A
genotype patients were more likely to improve over time.
Permutation analysis confirmed a significant effect of
rs4305746 on course of BPRS scores over time (p=0.007).
Haplotype analysis did not revealed any significant association
with clinical and safety scores at any time. Conclusion: A
possible association could exist between some genotypes in
TAAR6 and response to aripiprazole. However, several
limitations as the small sample size, the finding related to a
single scale and the possibility of false positive findings
require further investigations.

186 GRIA1, GRIA4, GRIA3 AND GRIK4 GENE
VARIANTS INFLUENCE HALOPERIDOL EFFICACY
AND SIDE EFFECTS IN A SAMPLE OF
SCHIZOPHRENIC PATIENTS
A. Serretti* (1), A. Drago (1), I. Giegling (2), A. Hartmann
(2), M. Schafer (2), H. Moller (2), D. De Ronchi (1), D.
Rujescu (2)
1. Institute of Psychiatry, University of Bologna, Italy 2.
Department of Psychiatry, Ludwig Maximilians University,
Munich, Germany
*alessandro.serretti@unibo.it
The unbalanced orchestration of the glutamate system is
thought to underlie the pathophysiology of schizophrenic
disorders. Consistently, there is evidence that the glutamate
system is pivotal to the effects of the antipsychotic treatments.
We investigated a set of 50 SNPs located in 11 genes coding
for subunits of glutamatergic receptors, as modulators of the
efficacy of haloperidol in a sample of 101 schizophrenic
patients. Furthermore, we investigated the possible impact on
the motor side effect profile associated with haloperidol
treatment. Patients were administered the PANSS and ESRS
tests at baseline and at day 3, 7, 14, 21 and 28. MANCOVA
analysis for repeated measures was applied along with the
FDR correction for multiple tests. T/T genotype at rs472792
(GRIA1) was found to be associated with a better response to
haloperidol treatment than G/T at PANSS positive at week 2
(f=6.18, p=0.001). C/C genotype at rs1461231 (GRIA1) was
found to be associated with a better response to treatment
compared to G/G genotype at PANSS positive scores at week
1 (f=7.32, p=0.00032). Those findings provide further support
to the glutamatergic theory of schizophrenia identifying
putative modulators of the antipsychotic effect of haloperidol.
187 CLINICAL PHARMACOGENETICS, REASONS
FOR THE SLOW APPLICATION AND REALISTIC
EXPECTATIONS
A. Serretti* (1)
1. Institute of Psychiatry, University of Bologna, Bologna,
Italy
*alessandro.serretti@unibo.it
The practical application of pharmacogenetics is not as
straightforward as expected, particularly in psychiatric
disorders. Despite the large benefit expected, only a very small
numbers of clinical applications are available. The reasons for
this are many, in particular the key questions are: Is science
robust enough for routine application? Are physicians and
patients ready? Are stakeholders (e.g. Government, insurance
industry, etc) ready to pay and implementing? What is the
position of the pharmaceutical industry? The presentation will
cover such aspects offering a coverage of present status and
realistic expectations in the field.
188 FURTHER EVIDENCE SUPPORTING THE
INFLUENCE OF BDNF ON THE OUTCOME OF
DEPRESSION. INDEPENDENT EFFECT OF BDNF
AND HARM AVOIDANCE
L. Mandelli* (1), M. Mazza (2), D. Marco (2), G. Martinotti
(2), D. Tavian (3), E. Colombo (3), S. Missaglia (3), G. Negri
(3), D. De Ronchi (1), R. Colombo (2, 3), L. Janiri (2)
1. University of Bologna, Italy 2. Catholic University of
Rome, Italy 3. Catholic University of Milan, Italy
*laura.mandelli@unibo.it
Brain derived neurotrophic factor (BDNF) is a candidate gene
for response to antidepressant treatment, as its product exerts
trophic effects on hippocampus and serotoninergic neurons.
Moreover, BDNF levels are increased by chronic
administration of antidepressants. However, response to
pharmacological treatments is moderated by both genetic and
individuals factors. In previous studies, we confirmed the
influence of the temperamental trait of Harm avoidance (HA)
on outcome from depression and we observed a significant
interaction with the promoter polymorphism of serotonin
transporter (5-HTTLPR). In the present study we aimed to
investigate the effect of 2 BDNF polymorphisms (rs6265 –
also called Val66Met– and rs11030104) on medium-term
outcome in a naturalistic sample of 86 depressed bipolar (BP)
spectrum patients, taking into account a number of clinical
features including HA. Rs6265 and rs11030104 were in full
linkage disequilibrium. Both single marker and haplotypes
analysis showed a significant association with severity of
depression at 6 months after intake. In particular, the
haplotype composed by the less frequent alleles A-C was
associated with a poorer outcome. HA maintained a significant
effect on depressive outcome, independently from BDNF
genotypes. However, HA’s influence appeared to be more
consistent in patients carrying the protective G-T combination
of alleles.

189 NDE1 VARIANT MODULATES OUTCOME FOR
DEPRESSION TREATED WITH ESCITALOPRAM
W. Hennah* (1), L. Muhonen (2), S. Saarikoski (2), J. Lahti
(3), L. Peltonen (1), J. Lönnqvist (2), H. Alho (2)
1. Institute for Molecular Medicine Finland FIMM, Nordic
EMBL Partnership for Molecular Medicine, Helsinki, Finland
2. National Institute for Health and Welfare, Department of
Mental Health and Substance Abuse Services, Helsinki,
Finland 3. University of Helsinki, Department of Psychology,
Helsinki, Finland
*william.hennah@thl.fi
In an analysis of public datasets it was demonstrated that there
are correlations between variants in the NDE1 gene and levels
of gene expression for existing targets for drugs developed for
depression and psychosis. One such target was HTR3A, which
is targeted by the drug memantine. In a clinical trial studying
major depressive disorder comorbid with alcohol dependence,
the effectiveness of memantine and escitalopram as treatments
were evaluated. This demonstrated that both treatments were
able to significantly reduce the baseline levels of depression
and anxiety. Here we have tested if the NDE1 variant
rs4781678 correlates with treatment outcome in depression.
We further tested for correlation dependent on drug treatment.
Outcome in depression was significantly improved in males
homozygous for the A allele of rs4781678 (p = 0.022).
However, this was dependent on treatment by escitalopram,
not the hypothesised memantine. Further bioinformatics and
studies of public datasets revealed that although NDE1
modulates expression levels of one of the nine targets for
memantine, it also modulates the expression level of the
principal metabolizing enzyme of escitalopram, CYP2C19. A
variant in strong LD with rs4781678 demonstrated that, in
human post-mortem brain tissue, carriers of the A allele have
significantly decreased amounts of CYP2C19 gene expression
(p = 0.029). We provide proof of concept that the DISC1
pathway could be used as a means to target treatment for
major mental illnesses, as hypothesised by Hennah and
Porteous, specifically by demonstrating that the NDE1 variant
rs4781678 modulates outcome for depression when treated
using escitalopram.
190 CIRCADIAN CLOCK GENES AND RESPONSE TO
ANTIDEPRESSANTS IN GENDEP
R. Keers* (1), R. Smith (1), R. Uher (1), P. Huezo-Diaz (1),
A. Elkin (1), M. Rietschel (2), T. Schulze (2), N. Henigsberg
(3), Z. Kovacic (3), A. Marusic (4), D. Kozel (5), O. Mors (6),
E. Larsen (5), J. Hauser (7), P. Czerski (7), W. Maier (8), J.
Perez (9), A. Placentino (9), J. Mendlewicz (10), D. Souery
(10), A. Farmer (11), P. McGuffin (12), I. Craig (11), K.
Aitchison (11)
1. Institute of Psychiatry at King’s College London, MRC
SGDP Centre, London, UK 2. Zentralinstitut für Seelische
Gesundheit, Division of Genetic Epidemiology in Psychiatry,
Mannheim, Germany 3. University of Zagreb, Croatian
Institute for Brain Research, Zagreb, Croatia 4. Institute of
Public Health, Ljubljana, Slovenia 5. University Hospital,
Department of Psychiatry, Risskov, Denmark 6. Aarhus
University Hospital, Department of Psychiatry, Risskov,
Denmark 7. Academic Dept of Medicine, Poznan, Poland 8.
University of Bonn, Anstalt des öffentlichen Rechts, für den
Fachbereich Medizin, Bonn, Germany 9. IRCCS, Centro San
Giovanni di Dio, FBF, Biological Psychiatry Unit and Dual
Diagnosis Ward, Brescia, Italy 10. Free University of
Brussels, Department of Psychiatry, Brussels, Belgium 11.
Farmer A.E.1, McGuffin P,1 Craig I.1, Aitchison K.J.1
Institute of Psychiatry at King’s College London, MRC SGDP
Centre, London, UK 12. Aitchison K.J.1 Institute of
Psychiatry at King’s College London, MRC SGDP Centre,
London, UK
*robert.keers@kcl.ac.uk
There is substantial individual variation in response to
antidepressants, and genetic variation may, in part, explain
these differences. A number of successful treatments for
depression have downstream effects on the circadian rhythm.
For example, the selective serotonin-reuptake inhibitor (SSRI)
fluoxetine has been shown to induce a phase shift in cell
culture studies. Functional polymorphisms in genes implicated
in the circadian rhythm may therefore be predictive of
response to antidepressants. GENDEP, a part-randomised drug
trial collected longitudinal data on the response of more than
800 patients undergoing treatment with either an SSRI
(escitalopram) or a tricyclic antidepressant (nortriptyline).
Two functional polymorphisms in genes associated with the
circadian clock were genotyped in this sample including a
variable number tandem repeat in PER3 and a SNP (rs180260)
in CLOCK. Both polymorphisms moderated response to both
drugs and these effects were age-dependent. This suggests that
circadian clock genes may not only be important in the
aetiology of mood disorders but also in the prediction of
response to antidepressants.

191 GENETIC STUDY OF
CATECHOL-O-METHYL-TRANSFERASE IN
TARDIVE DYSKINESIA
C. Zai* (1), D. Mueller (1), D. Mueller (1), V. de Luca (1), X.
Ni (1), D. Sibony (1), A. Aristotle (1), H. Meltzer (2), J.
Lieberman (3), S. Potkin (4), G. Remington (1), J. Kennedy
(1)
1. Centre for Addiction and Mental Health 2. Psychiatric
Hospital at Vanderbilt University 3. New York State
Psychiatric Institute, Columbia University Medical Centre 4.
University of California, Irvine
*clement_zai@camh.net
Tardive dyskinesia (TD) is a severe motor side effect of
long-term antipsychotic medication. Changes in dopamine
neurotransmission have been implicated in the etiology of
TD. Catechol-O-Methyl-Transferase (COMT) is an enzyme
that metabolizes dopamine. The functional Val158Met
polymorphism has been associated with TD; however, the
small effect size reported in a recent meta-analysis suggests
that additional genetic factors in COMT may contribute to TD
development. We investigated four single-nucleotide
polymorphisms in addition to the functional Val158Met
variant in the COMT gene for association with TD. Three of
the polymorphisms have been associated with pain sensitivity
and COMT enzymatic activity (Nackley et al, 2006). We
genotyped the five COMT polymorphisms in our sample of
schizophrenia/schizoaffective disorder patients (n=196
Caucasians and 30 African Americans) using commercially
available assays and performed statistical analyses, which
included comparing the severity of TD among patients
carrying different COMT variants. We found the rs165599
marker in the 3’ untranslated region of the COMT gene to be
marginally associated with TD occurrence. We did not find a
significant association of the other four tested polymorphisms
or their combinations with TD in our samples. When we
included age and sex as covariates in the analyses, the results
were not significant. We will be performing an updated
meta-analysis of the Val158Met polymorphism, including
additional studies. The results with our sample suggest that
the COMT gene is not a major factor in TD, but further studies
with additional markers in larger clinical samples are required.
192 ASSOCIATION OF OPRM1 DNA VARIANTS
GENETIC CORRELATIONS IN HEROIN ADDICTED
PATIENTS UNDERGOING NALTREXONE IMPLANT
TREATMENT.
A. Scott* (1, 2), N. Morris (1), G. Hulse (1), D. Wildenauer
(1), S. Schwab (1, 2, 3)
1. School of Psychiatry and Clinical Neurosciences,
University of Western Australia 2. Centre for Medical
Research and Western Australian Institute for Medical
Research, University of Western Australia 3. School of
Medicine and Pharmacology, University of Western Australia
* ascott@cyllene.uwa.edu.au
While environmental factors are likely to contribute to
different degrees of addiction, it is becoming clear that
susceptibility is strongly influenced by an individual’s genetic
makeup. Heroin has one of the highest levels of genetic
variance compared to other illicit drugs, in particular
marijuana, stimulants, sedatives and psychedelics. Much
research into heroin addiction genetics has focussed on the
µ-opioid receptor (OPRM1), which is the primary target for
heroin action. The coding region polymorphism A118G
(Asn40Asp) has been the primary focus of interest. This
genetic variant has recently been associated with treatment
outcome in alcoholism using naltrexone. We have genotyped
this polymorphism in a large sample of heroin addicted
patients who have been treated with naltrexone implants. In
total a cohort of 750 heroin addicted Caucasian patients have
been collected. Phenotypic data such as naltrexone serum
levels after implant and treatment outcome as measured by
repeated contact with the clinic was established. High
throughput Taqman assays available on demand from Applied
Biosystems have been used for genotyping, and association of
this polymorphism with treatment outcome in heroin addiction
was attempted. Due to the large number of patients, our study
has a high power for showing association with genetic
variants. The unique phenotypic characterization of our study
allows conclusion on treatment outcome using naltrexone
implants in heroin addiction.

193 ALTERATION IN THE RATIO OF BAX/BCL-2
EXPRESSION LEVEL IN MODIFIED
ELECTROCONVULSIVE THERAPY
A. Tsutsumi*, S. Kawashige, T. Kanazawa, H. Kikuyama, J.
Koh, H. Yoneda
* psy063@poh.osaka-med.ac.jp
Schizophrenia is generally considered as a
neurodevelopmental disorder. Evidences for progressive
clinical deterioration and subtle neurostructural changes
following the onset of psychosis has led to the hypothesis that
apoptosis may contribute to the pathophysiology of
schizophrenia. Among the antipsychoticdrugs, olanzapine may
have neuroprotective effects, whereas haloperidol was
apparently neurotoxic through some mechanism apoptosis
(Kim NR et al: 2008). Modified-electroconvulsive therapy
(m-ECT) isa widely used and efficient treatment in psychiatry,
although the basis for its therapeutic effect is still unknown.
There are some reports which indicate therelation with m-ECT
and TNF-alpha (HestadKA et al: 2003). We had also
investigated the mRNA expression levelsof TNF-alpha, and
found out the relationship between TNF-alpha and efficacy in
the schizophrenia. TNF-alpha serves as potent inductors of
apoptosis and changes the ratio of Bax-/Bcl-Xl expression in
human (Szuster-CiesielskaA et al: 2008). Therefore, we
hypothesized that therapeutic mechanism of m-ECT might be
associated with apoptosis. We investigated mRNA expression
levels of Bax and Bcl-2 to see if there is relationship with
efficacy in the schizophrenia treated with m-ECT.
194 ALTERATION IN GSK-3β MRNA EXPRESSION
ON THE TREATMENT BOTH BY SDAS AND BY
M-ECT FOR SCHIZOPHRENIA
S. Kawashige*, A. Tsutsumi, T. Kanazawa, H. Kikuyama, J.
Koh, H. Yoneda
* seiyart@gmail.com
Akt-GSK-3β signaling has been recently reported as
associated not only with bipolar disorder, but also with
schizophrenia. Glycogen synthase kinase-3β (GSK-3β) is
considered as a target of lithium. Emamian et al. reported a
decrease in AKT1 protein levels and Ser9 phosphorylation of
GSK-3β in the peripheral lymphocytes and brains of
schizophrenia patients. Moreover, increased serine
phosphorylation of GSK-3β in brain of mouse was also
induced by electroconvulsive seizure treatment. (Roh MS et
al. 2003). We investigate the alteration of GSK-3β in
schizophrenia with gene expression analysis (RT-PCR). With
employing the mRNA derived from peripheral blood of
schizophrenia treated by SDAs (n=10), by m-ECT (n=10) and
control (n=3), expression levels are determined at the points of
every four weeks (0W, 4W, 8W). The role of GSK-3β will be
discussed in the conference.
195 CANNABINOID TYPE-1 RECEPTOR GENE
POLYMORPHISMS ARE NOT ASSOCIATED WITH
OLANZAPINE-INDUCED WEIGHT GAIN
Y. Park (1), J. Choi (2), S. Kang (1), L. Kim (1), H. Lee* (1)
1. Inje University College of Medicine 2. Korea University
College of Medicine
* leehjeong@korea.ac.kr
Objective: Olanzapine is an atypical antipsychotic known to
cause considerable weight gain. The CNR1 cannabinoid
receptor is involved in energy balance control, stimulating
appetite and increasing body weight. In the present study, we
investigated the 1359G/A (rs1049353), 4895A/G (rs806368),
and rs4707436 polymorphisms in the CNR1 gene and weight
gain in a Korean schizophrenic patients receiving olanzapine
treatment. Methods: Weight and height measurements were
obtained prior to starting olanzapine and measured again after
long-term treatment in 79 schizophrenic patients. Genotyping
for the CNR1 polymorphisms were performed using
PCR-RFLP methods. Results: There were no association
between three CNR1 gene polymorphism and body weight
change from baseline to the endpoint after olanzapine
treatment (p>0.05). There were also no significant differences
in genotype or allele frequencies between the severe
weight-gain (more than 7%) and less weight-gain (less than
7%) groups. The haplotype analyses did not show the
significant differences between two groups. Conclusion:
Within the limitations imposed by the size of the clinical
sample, our findings suggest that CNR1 gene polymorphisms
may be not associated with olanzapine-induced weight gain.

196 NO ASSOCIATION BETWEEN IL-10 AND
TNF-alpha GENES POLYMORPHISMS AND TARDIVE
DYSKINESIA IN SCHIZOPHRENIA
S. Kang (1), J. Choi (1), H. Lee* (1), L. Kim (1)
1. Korea University College of Medicine
* leehjeong@korea.ac.kr
Objective: Cytokines has been reported to be associated with
several psychiatric illnesses including schizophrenia.
Antipsychotic treatment has also been involved in the altered
levels of some cytokines. There are emerging evidences
suggest that the development of TD is related to the oxidative
stress, excitotoxicity, and immune activation. The purpose of
this study is to investigate whether single-nucleotide
polymorphisms (SNPs) of interleukin(IL)-10 and tumor
necrosis factor(TNF)-α genes are associated with the
susceptibility of TD and schizophrenia. Methods: Two
hundred and nine unrelated Korean schizophrenic patients (83
TD and 126 non-TD patients) and two hundred and twelve
normal healthy controls participated in the present study. The
schizophrenic participants consisted of patients with (n=83)
and without (n=126) TD who were matched for antipsychotic
drug exposure and other relevant variables. All the
schizophrenic patients met the criteria for a diagnosis of
schizophrenia as determined by board-certified psychiatrists
using the Korean version of the Structured Clinical Interview
for the fourth edition of the Diagnostic and Statistical Manual
of Mental Disorders. TD was diagnosed based on the
Abnormal Involuntary Movement Scale (AIMS). The IL-10
gene -1082G/A and TNF-α gene -308G/A SNPs were
analyzed by polymerase chain reaction (PCR)-based methods.
Results: The frequencies of genotypes (?2=2.65, p=0.263) of
the IL-10 gene -1082G/A SNP and the frequencies of
genotypes (?2=0.13, p=0.715) of the TNF-α gene -308G/A
SNP did not differ significantly between schizophrenic
patients with and without TD. The distribution of genotype at
two polymorphisms between the schizophrenic patients and
controls was not significantly different, either (p>0.05). MDR
analysis did not show a significant interaction between the
IL-10 gene and TNF-α gene and susceptibility to TD and
schizophrenia (p>0.05) Conclusions: This is the first study on
the association of antipsychotics-induced TD with gene
polymorphisms in cytokine production. These results suggest
that the IL-10 gene -1082G/A and TNF-α gene -308G/A SNPs
are not associated with TD and schizophrenia in a Korean
population. Further association studies of TD with other
candidate genes for cytokines would help us understand the
pathophysiological mechanisms of TD.
197 INVOLVEMENT OF THE ATRIAL NATRIURETIC
PEPTIDE TRANSCRIPTION FACTOR GATA4 IN
ALCOHOL DEPENDENCE, RELAPSE RISK, AND
TREATMENT RESPONSE TO ACAMPROSATE
S. Witt (1), F. Kiefer (2), J. Frank (1), A. Richter (2), J.
Treutlein (1), T. Lemenager (2), M. Nöthen (3), S. Cichon (3),
A. Batra (4), M. Berner (5), N. Wodarz (6), U. Zimmermann
(7), R. Spanagel (8), K. Wiedemann (9), M. Smolka (10), A.
Heinz (10), K. Mann (2), M. Rietschel* (1)
1. Dept. of Genetic Epidemiology in Psychiatry, Central
Institute of Mental Health, Mannheim 2. Dept. of Addictive
Behavior and Addiction Medicine, Central Institute of Mental
Health, Mannheim 3. Department of Genomics, Life & Brain
Center, University of Bonn 4. Dept. of Psychiatry and
Psychotherapy, University Göttingen 5. Dept. of Psychiatry
and Psychotherapy, University Freiburg 6. Dept. of Stem Cell
Biology, University Göttingen 7. Dept. of Psychiatry and
Psychotherapy, Technical University Dresden 8. Dept. of
Psychopharmacology, Central Institute of Mental Health,
Mannheim 9. Dept. of Psychiatry and Psychotherapy,
University Medical Center Hamburg-Eppendorf 10. Dept. of
Psychiatry and Psychotherapy, Charite Berlin
* marcella.rietschel@zi-mannheim.de
Context: Identifying genes contributing to relapse and
treatment response will improve our understanding of the
mechanisms underlying alcohol dependence and will yield
treatment targets for personalized medicine. Objective: To
determine whether 15 single nucleotide polymorphisms
(SNPs), linked to alcohol dependence by a recent
genome-wide association (GWA) and replication study, are
associated with relapse behavior. Secondary objective: To
examine whether those associations can be linked to
pharmacological treatment response. Design:
Genotype-phenotype association study and pharmacogenetics
in alcohol dependent patients: Fifteen SNPs were genotyped
and tested for an association with relapse during twelve weeks
of treatment. Setting: Five academic medical centers in
Germany Patients: 374 participants with a DSM-IV diagnosis
of alcohol dependence that underwent a randomized,
double-blind, placebo-controlled trial with acamprosate,
naltrexone or placebo. Main Outcome Measures: Primary:
Association between 15 SNPs identified by a recent GWA
study on alcohol dependence and relapse. Secondary:
Treatment response with naltrexone and acamprosate in
association with these genetic variations. Post-hoc:
Measurement of a trial natruiuretic peptide (ANP) in plasma.
Results: SNP rs13273672, an intronic SNP in GATA4, was
significantly associated with relapse within a 90-days medical
treatment period (P < .01). Subsequent pharmacogenetic
analysis showed that this association was mainly based on
patients treated with acamprosate (P

198 CYP2D6 AND CYP2C19 IN A BRAZILIAN
POPULATION: POTENTIAL ROLE IN IMPROVING
TREATMENT OUTCOMES IN MAJOR DEPRESSION.
C. Prado (1), R. Moreno (2), W. Gattaz (1), E. Ojopi* (1)
1. Laboratório de Neurociências (LIM 27), Institute of
Psychiatry, University of São Paulo (USP), São Paulo, Brazil.
2. Grupo de Estudos de Doenças Afetivas (GRUDA), Institute
of Psychiatry, University of São Paulo (USP), São Paulo,
Brazil.
* elida@usp.br
The enzymes of cytochrome P450 (CYP), mainly CYP2D6
and CYP2C19 are known for metabolizing approximately half
of the 200 more often prescript medications. The CYP2D6
enzyme by itself is responsible for the metabolism of
approximately 25% of these medications, especially
antidepressants (SSRIs e TCAs). At present, more than 90
different allelic variants and sub variants in the CYP2D6 gene
are known and there are only four major phenotypes: poor,
intermediate, extensive, and ultrarapid metabolizers, while for
the CYP2C19 gene, the possible phenotypes are: PMs, EMs
and UMs. The enzymes of cytochrome P450 (CYP), mainly
CYP2D6 and CYP2C19 are known for metabolizing
approximately half of the 200 more often prescript
medications. The CYP2D6 enzyme by itself is responsible for
the metabolism of approximately 25% of these medications,
especially antidepressants (SSRIs e TCAs). This study aimed
to explore the influence of variation in CYP2D6 and
CYP2C19 genes on treatment response to antidepressants in a
Brazilian sample of patients with Major Depression. Up to
now 73 samples of patients with Major Depression and 90
control samples were genotyped for the following alleles:
CYP2D6*1, *2, *3, *4, *6, *9, *10, *15, *17, *29, *34, *35,
*40, *41, and CYP2C19*1, *2, *3, and *17. Genotyping was
performed by real-time PCR allelic discrimination. The
CYP2D6*5 allele and the number of copies of the gene
CYP2D6 were identified by Real-Time PCR. The Hamilton
scale of evaluation for depression (HAM-D) was used to
determine the clinic course of response to the treatment and
the adverse affects were also registered. As described in other
studies in different populations alleles CYP2D6*1 and
CYP2D6*2 were the most frequent in our sample (42,8 e
24.31%, respectively), followed by the alleles CYP2D6*4
(11,64%) and CYP2D6*41 (5,82%). For the CYP2C19 gene,
our the allele CYP2C19*1 is the most frequent (60%),
followed by the allele CYP2C19*17 (24%) and the
CYP2C19*2 (16%). To our knowledge the CYP2C19*17
allele was evaluated in a Brazilian population for the first
time. We have found positive correlations genotype-phenotype
although possible jeopardized because there was heterogeneity
among medications. The future of ‘personalized prescription’
in psychiatry requires consideration of pharmacogenomic
testing and environmental and personal variables that
influence pharmacokinetic and pharmacodynamic drug
response for each individual drug used by each patient.
Financial support: CNPq and ABADHS.
199 GENETIC VARIATION IN ERBB4 GENE
ASSOCIATED WITH RESPONSE TO PALIPERIDONE
TREATMENT IN PATIENTS WITH SCHIZOPHRENIA
D. Fu* (1), D. Wang (1), Q. Li (1), J. Berwaerts (1), X. Wu
(1), R. Favis (1), M. Haas (1), N. Turner (2), H. Chung (2), L.
Alphs (2), H. Manji (1), R. Twyman (1), N. Cohen (1)
1. J&J PRD 2. Ortho-McNeil Janssen Scientific Affairs
* DFu@its.jnj.com
Background: Schizophrenia is a heterogeneous disorder with
inter-individual differences in its onset, symptoms, and
treatment responses. For these reasons, response to the novel
antipsychotic compound, paliperidone, is likely to be
influenced by individual genetic variation. We therefore
conducted a study to identify genes that may contribute to the
variation in the treatment response to paliperidone. Method: A
CNS chip containing over 25,000 single nucleotide
polymorphisms in 1,204 candidate genes related to
pathophysiology and treatment response of a wide range of
psychiatric disorders was developed. 684 patients
experiencing an acute exacerbation of schizophrenia from the
paliperidone treatment arms of 3 paliperidone-ER pivotal trials
and 1 paliperidone palmitate phase 2 trial were genotyped
using the CNS chip. Genetic associations were tested with a
general linear model using the absolute changes from baseline
to end point in their PANSS total score, and in PANSS factor
scores, as outcome variables. Results: SNP rs6435681 in the
ErbB4 gene was associated with PANSS total score
improvement from baseline to end point (Bonferroni adjusted
p-value: 0.02). Patients carrying the GG or GA genotypes
(N=659) had a significantly greater average reduction in
PANSS total score than AA carriers (N=25). Significant
association of the ErbB4 SNP in the same direction was not
observed in the placebo arms (N=258) or the olanzapine active
control arms (N=235) across trials. Conclusion: These
findings provide the first evidence that genetic variation in the
ErbB4 gene (associated with neuregulin regulation) may
differentially affect treatment response to paliperidone in
acutely exacerbated schizophrenic patients.

200 GAMMA-AMINOBUTYRIC ACID RECEPTOR
GENE POLYMORPHISMS AND
ANTIPSYCHOTICS-INDUCED TARDIVE
DYSKINESIA
J. Choi (1), S. Kang (1), H. Lee* (1)
1. Korea University
* leehjeong@korea.ac.kr
Background: Gamma-aminobutyric acid (GABA)
insufficiency has been reported to be related with the TD
susceptibility. Arinami et al. reported that the GABA receptor
signaling pathway may be involved in the pathophysiology of
TD by genome wide association study. We conducted a
genetic association analysis between GABA related genes and
TD in Korean schizophrenic patients. Methods: Applying
gene-based association analysis, we selected two
polymorphisms in GABRG3 (c-3 subunit of GABA-A
receptor) and SLC6A11 (GABA transporter 3). Two SNP
were analyzed by PCR-based methods in 99 schizophrenic
patients with TD and 164 schizophrenic without TD who were
matched for antipsychotic drug exposure and other relevant
variables. Results: Among the two variants, SCL6A11
genotypes distribution showed a significant difference
between TD and non-TD (X2=12.59, p=0.002), however,
GABRG3 genotype distribution was not associated with TD
(X2=2.65, p=0.27). Conclusions: These results suggest that
SLC6A11 gene polymorphism was associated with the
increased susceptibility to TD in patients with schizophrenia
in the Korean populations.
201 THE CIRCADIAN CLOCK INFLUENCES
LITHIUM TREATMENT RESPONSE IN BIPOLAR
DISORDER
M. McCarthy* (1), T. Shekhtman (2), R. McKinney (1), D.
Kripke (3), J. Kelsoe (1)
1. Department of Psychiatry, University of California San
Diego, La Jolla, CA 2. VA San Diego Healthcare System, San
Diego, CA 3. Scripps Clinic Sleep Center, La Jolla, CA
* mmccarthy@ucsd.edu
Several circadian clock genes are lithium responsive, and
lithium treatment for bipolar disorder is effective in part
because of its ability to correct disturbances in circadian
rhythms. However, treatment response to lithium varies. We
hypothesized that variants in circadian clock genes may
contribute to lithium treatment outcomes in bipolar disorder.
Similarly, we hypothesized that differences in daily
sleep/activity cycles may predict lithium response. We
identified 164 bipolar disorder patients who responded well to
lithium, and 154 who responded poorly based on retrospective
assessment. These subjects were genotyped for 29 SNPs
across 13 core clock genes. In a subset of these patients, we
administered the basic language morningness questionnaire
(BALM) to 50 lithium responders and 46 lithium
non-responders. Subjects who scored in the phase delayed
range on the BALM had a better response to lithium than
subjects in the normal or phase advanced ranges. Genetic
analysis revealed the rare variant of the intronic SNP
rs2071427 in the Rev-Erbα gene was associated with a
favorable lithium response. The SNPs rs1801260 (3111 T/C)
and rs34897046 in the gene Clock were also significantly
associated with response to lithium. Allele-specific gene
expression at the Clock locus in heterozygotes for rs1801260
was measured in lymphoblastoid cells. This SNP did not
confer an allelic expression imbalance either under baseline or
lithium treated conditions. From these data a link between
lithium response and genetic variation within the circadian
clock is supported but the precise biological mechanism
remains unknown.

202 OXYTOCIN AND PROLACTIN SYSTEM
POLYMORPHISMS IN CHILDHOOD-ONSET MOOD
DISORDERS
J. Strauss* (1), N. Freeman (1), S. Shaikh (1), A. Vetro (2),
E. Kiss (2), K. Kapornai (2), C. George (3), E. Dempster (4),
C. Barr (5), M. Kovacs (3), J. Kennedy (1)
1. Centre for Addiction and Mental Health 2. Szeged
University Medical Faculty 3. Western Psychiatric Institute
and Clinic 4. Institute of Psychiatry 5. Toronto Western
Research Institute
* john_strauss@camh.net
Background: Oxytocin (OXT) and prolactin (PRL) are
neuropeptide hormones that are involved in the stress response
and social affiliation. They interact with the serotonin system.
Reports in the literature indicate that human serum OXT and
PRL levels are associated with depressive symptoms and
related phenotypes. In a genetic association study with a
family-based design, we examined single nucleotide
polymorphisms (SNPs) at the loci for OXT, PRL and their
receptors (OXTR and PRLR) for association with
childhood-onset mood disorders (COMD). Methods: Using
lymphocyte DNA from 678 families recruited from Hungary,
we genotyped sixteen SNPs at OXT, PRL and their receptors
to test for association with COMD. Results: We observed no
statistically significant associations for OXTR, PRL, and
PRLR SNPs. Two of three SNPs 3' of the OXT gene were
associated with COMD (p < 0.02), were significant after
spectral decomposition, but were not significant after
additionally adjusting for the number of genes tested.
Supplementary analyses demonstrated significant transmission
bias to daughters, but not sons, for two OXT SNPs -
rs2740210 (p = 0.04); rs2770378 (p = 0.02). Conclusions: We
have examined OXT and PRL system gene variants, with no
evidence of statistically significant association after multiple
testing corrections. We found a nonsignificant trend between
OXT SNPs and COMD. Additional analyses suggest two
OXT SNPs have transmission bias to daughters, consistent
with evidence in the literature that OXT is regulated by
estrogen.
SCHIZOPHRENIA
203 NO ASSOCIATION BETWEEN THE PPARG GENE
AND SCHIZOPHRENIA IN A BRITISH POPULATION
A. Mathur*, M. Law, I. Megson, D. Shaw, J. Wei
* aditi.mathur@uhi.ac.uk
It has consistently been reported that patients with
schizophrenia have an increased risk of type-2 diabetes. To
investigate a genetic link between these 2 diseases, the
combined effects of the PLA2G4A, PTGS2 and PPARG genes
were tested among 221 British nuclear families consisting of
fathers, mothers and affected offspring with schizophrenia. A
total of 10 single nucleotide polymorphisms (SNPs) were
tested and the likelihood-based association analysis for nuclear
families was used to analyse genotyping data. Eight SNPs
detected across the PPARG gene did not show allelic
association with schizophrenia; a weak association was
detected at rs2745557 in the PTGS2 locus (c2=4.19, p=0.041)
and rs10798059 in the PLA2G4A locus (c2=4.28, p=0.039)
but these associations did not survive after 10000
permutations to correct the p-value (global p=0.246). The
gene-gene interaction test did not show any evidence of either
cis-phase interactions for the PLA2G4A and PTGS2
combinations or a trans-phase interaction for the PLA2G4A
and PPARG combinations. The PPARG gene has been
reported to be strongly associated with type-2 diabetes, but the
present study did not support the hypothesis that the PPARG
gene may also play an important role in the development of
schizophrenia.

204 ASSOCIATION STUDY OF EFNB2 GENE AND
SCHIZOPHRENIA IN THE CHINESE POPULATION
R. Zhang (1), N. Zhong (1), X. Liu (2), H. Yan (2), C. Qiu (2),
Y. Han (1), W. Wang (1), W. Hou (1), Y. Liu (1), C. Gao (3),
T. Guo (4), S. Lu (1), H. Deng (2), J. Ma* (1)
1. Department of Genetics and Molecular Biology, Xi’an
Jiaotong University School of Medicine 2. School of Life
Science & Technology, Xi’an Jiaotong University 3. First
Affiliated Hospital, Xi’an Jiaotong University School of
Medicine 4. National Institutes of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health
* tigermajie@yahoo.com.cn
Recently, evidence of linkage of schizophrenia to
chromosome 13q22-q34 has been demonstrated in multiple
studies. Based on structure and function, EFNB2 may be
considered as a compelling candidate gene for schizophrenia
on chromosome13q33. We genotyped three single-nucleotide
polymorphisms (SNPs: rs9520087, rs11069646, and
rs8000078) in this region in 846 Han Chinese subjects (477
cases and 369 controls). Significant association between an
allele of marker rs9520087 and schizophrenia was found
(P=0.0044). Furthermore, since no LD was observed in the
three SNPs linkage disequilibrium estimation, all three SNPs
were used in multiple haplotype analysis, and a strongly
significant difference was found for the common haplotype
TTC (P=0.004). Overall our findings indicate that EFNB2
gene may be a candidate susceptibility gene for schizophrenia
in the Han Chinese population, and also provide further
support for the potential importance of the NMDA receptor
pathway in the etiology of schizophrenia.
205 THE SIGNIFICANT GENETIC REGIONS OF
SCHIZOPHRENIA SUSCEPTIBILITY GENE,
CALCIUM CHANNEL, VOLTAGE-DEPENDENT,
GAMMA SUBUNIT (CACNG2)
Y. Liu* (1), C. Liu (2), C. Fann (3), T. Liu (4), S. Tsai (5), U.
Yang (6), P. Hsu (6), W. Yang (3), C. Wen (2), H. Hwu (2)
1. Division of Mental Health and Addiction Medicine,
Institute of Population Health Sciences, National Health
Research Institutes, Taiwan 2. Department of Psychiatry,
National Taiwan University Hospital and National Taiwan
University College of Medicine, Taiwan 3. Institute of
Biomedical Sciences, Academia Sinica, Taiwan 4. Genome
Research Center, National Yang-Ming University, Taiwan 5.
Division of Molecular and Genomic Medicine, National
Health Research Institutes, Taiwan 6. Institute of
Bioinformatics, National Yang-Ming University, Taiwan
* ylliou@nhri.org.tw
Calcium Channel, Voltage-Dependent, Gamma Subunit
(CACNG2) is a schizophrenia susceptibility gene. In our
previous study, the single nucleotide polymorphism (SNP)
fine mapping in the region of chromosome 22 showed a
statistically significant association at the intron 1 region of
CACNG2. In a later direct sequencing study for risk SNP of
CACNG2 in schizophrenia, a total of 4 SNPs were found
fitting the criteria of the least minor allele frequency
differences above 2% between normal controls and
schizophrenia. These four SNPs (rsCACNG2-3,
rsCACNG2-16, rsCACNG2-18, and rsCACNG2-20) were
further genotyped on 600 normal controls and 912
schizophrenic patients. A risk SNP of rsCACNG2-3 located at
intron 2 showed statistically significant association with
schizophrenia (odds ratio = 1.2476, p=0.008). The normal
controls and the schizophrenic patients had the same
haplotypes structure. Furthermore, the risk SNP demonstrated
a statistically significant association with the subgroups of
deficit endophenotypes of sustained attention, assessed by
continuous performance test (CPT; p=0.0015 for degraded and
p=0.003 for undegraded CPT), and executive function,
assessed by the Wisconsin Card Sorting Test (WCST;
p=0.0143 for categorical achievement and p=0.0133 for
perseverative error). We conclude that the intron 2 genetic
region at CACNG2 may be a true susceptibility region risk for
schizophrenia.

206 THE OXYTOCIN AND VASOPRESSIN GENES AS
CANDIDATES FOR SCHIZOPHRENIA IN A LARGE
INBRED ISRAELI ARAB PEDIGREE
T. Omri* (1), K. Kyra (1), K. Osnat (1), K. Mira (2), L.
Bernard (1), A. Hamdan (3), K. Yoav (1)
1. Biological Psychiatry Laboratory, Department of
Psychiatry, Hadassah-Hebrew University Medical Center,
Jerusalem, Israel 2. The Center for Genomic Technologies,
Institute of Life Sciences, Hebrew University, Jerusalem,
Israel 3. Regional Mental Health Center, Taibe, Israel
* omri.teltsh@mail.huji.ac.il
We study the genetics of schizophrenia in a large, multiplex
Israeli Arab pedigree. The use of rare pedigrees, in which risk
genetic variants have a major effect on the disorder
occurrence, has been proven as a beneficial strategy in studies
of other complex disorders. By performing a genome wide
linkage analysis for schizophrenia in this pedigree, we have
previously demonstrated evidence for linkage on chromosome
20p13. A haplotype of 3 markers in this region, 1.8Mb in
length and containing strong candidate genes for
schizophrenia, was found to be shared by most affected
pedigree members. More recently, we have sequenced the
coding domain and flanking regions of four of these genes,
among both affected and healthy individuals from the
pedigree. Our sequencing results led us to concentrate on the
genes OXT and AVP. The hormones encoded by these genes,
Vasopressin and Oxytocin, are known to be involved in social
behavior. Evidences exist for their association with OCD and
autism. In the current study we completed sequencing of the
intronic regions of OXT and AVP, as well as four additional
regulatory sites of these genes. 7 rare SNPs were identified
and studied in the whole pedigree. Four SNPs were
significantly associated with schizophrenia. A 7-SNP
haplotype was also significantly associated with disease
status. We also study these genes contribution to
schizophrenia, by genotyping the same SNPs in other samples,
in order to replicate our findings. In addition, the possible
effect of these SNPs on expression of the genes will also be
studied.
207 PRIORITIZING CANDIDATE GENES FOR
SCHIZOPHRENIA: CONVERGENCE OF
ASSOCIATION AND GENE EXPRESSION ANALYSES
P. D. Shilling* (1), T. A. Greenwood (1), D. L. Braff (1), G.
L. Light (1), K. S. Cadenhead (1), M. A. Geyer (1), J. Sprock
(1), N. R. Swerdlow (1)
1. University of California, San Diego
* pshilling@ucsd.edu
We had previously developed a database (Shilling, et al., Biol
Psych 2008) composed of gene expression values in the
nucleus accumbens (NAC) for two rat strains that exhibit
differential prepulse inhibition (PPI) responsiveness to the
dopamine agonist, apomorphine (APO). We used this database
to prioritize 22 candidate genes, identified using a custom
COGS/UCSD SNP chip, that are significantly associated with
schizophrenia and/or at least one of the PPI-related
endophenotypes examined: % PPI, startle magnitude, and
habituation (Greenwood et al. 2008), for further analysis.
Gene expression was measured with Affymetrix 230 2.0 chips.
Twenty of the 22 genes identified by association analysis were
represented on this gene chip. Gene expression of these 20
genes in the NAC was analyzed in an animal model of
differential PPI sensitivity to APO in Long Evans vs. Sprague
Dawley rats. Statistical analysis of microarrays (SAM) was
employed to identify significant between strain differences in
expression using a false discovery rate < 5 %. SAM analysis
revealed that 10 (50%) of the significantly associated genes
also exhibited significant gene expression differences. These
genes include COMT, NRG1, DAT and GRIN2B. In addition,
Ingenuity Pathway Analysis indicated that glutamate and
dopamine receptor signaling pathways were significantly
overrepresented. Many of the genes that were associated with
schizophrenia and/or PPI-related endophenotypes were also
differentially expressed across rat strains exhibiting
differences in PPI sensitivity to a dopamine agonist. This
convergent translational approach could facilitate the
identification of genes that contribute to the development of
schizophrenia.Supported by MH42228 and MH68366

208 NEXT GENERATION SEQUENCING OF THE
DISC1 LOCUS
P. Thomson* (1, 2), M. De La Bastide (3), A. McRae (4), D.
Soares (1, 2), J. Parla (3), K. Ramakrishnan (1, 2), W. Hennah
(1, 5), K. Evans (1, 2), K. Millar (1, 2), S. Harris (1, 2, 6), S.
Macgregor (4), S. Brown (1, 2), D. Rebolini (3), L. Cardone
(3), M. Bell (3), J. Watson (3), J. Starr (7), I. Deary (6), D.
Blackwood (1, 2, 8), W. Muir (1, 2, 8), P. Visscher (4), W.
McCombie (3), D. Porteous (1, 2, 6)
1. Medical Genetics Section, University of Edinburgh,
Edinburgh, EH4 2XU, UK 2. Molecular Medicine Centre,
Western General Hospital, Crewe Road, Edinburgh, EH4
2XU, UK 3. Cold Spring Harbor Laboratory, Cold Spring
Harbor, New York 11724, USA 4. Queensland Statistical
Genetics, Queensland Institute of Medical Research, 300
Herston Road, Brisbane, QLD, 4029, Australia 5. Institute for
Molecular Medicine Finland FIMM, Nordic EMBL
Partnership 6. Centre for Cognitive Ageing and Cognitive
Epidemiology, Department of Psychology, University of
Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK 7.
Centre for Cognitive Ageing and Cognitive Epidemiology,
Geriatric Medicine Unit, University of Edinburgh, Royal
Victoria, Craigleith Road, Edinburgh, EH4 2DN, UK 8.
Department of Psychiatry, Royal Edinburgh Hospital,
Morningside Park, Edinburgh, EH10 5HF, UK
* pippa.thomson@ed.ac.uk
DISC1 was first identified as a candidate for psychiatric
illness through segregation of a t(1:11) translocation in a large
Scottish family. This was confirmed by linkage of variants in
DISC1 to psychiatric illness in further families from Scotland
and Finland. In addition, many, although not all, association
studies of DISC1 and the upstream gene, TSNAX, have
detected association to a range of mental illnesses and
cognitive phenotypes in multiple populations worldwide.
Results from genome-wide association studies performed to
date have been more equivocal. Only weakly significant
p-values have been detected in these large scale studies for
DISC1 and other strong candidate genes for schizophrenia,
most likely due to genetic heterogeneity. In line with this a
recent publication by Song et al. suggested that DISC1 exons
may harbour multiple rare structural variants conferring
susceptibility to schizophrenia.In order to examine the full
range of variants in the 550 kb TSNAX/DISC1 region, we
have sequenced up to 300 subjects for each of schizophrenia,
bipolar disorder, depression, and healthy controls by high
throughput sequencing on the Illumina Genome Analyzer
platform. In contrast to previous studies, we have sequenced
the entire genomic locus including exons, introns, promoters
and intergenic regions.The results identify multiple new
variants and confirm some of those identified in patient
samples by Song et al. Bioinformatic analysis allows us to
make structure-function predictions that support a causal role
for these rare variants in major mental illness.
209 ANALYSES OF GENE EXPRESSION PROFILE
AND ABERRANT SPLICING IN SCHIZOPHRENIA
USING EXON ARRAY
Y. Ito* (1), S. Yamada (2), B. Aleksic (1), I. Kushima (1), Y.
Nakamura (1), A. Yoshimi (3), T. Nagai (3), Y. Noda (2), K.
Ohno (5), N. Ozaki (1)
1. Department of Psychiatry, Nagoya University Graduate
School of Medicine 2. Division of Clinical Sciences and
Neuropsychopharmacology, Graduate School of
Pharmaceutical Sciences, Meijo University 3. Department of
Neuropsychopharmacology and Hospital Pharmacy, Nagoya
University Graduate School of Medicine 4. Department of
Neurogenetics, Nagoya University Graduate School of
Medicine
* y-ito@med.nagoya-u.ac.jp
The contribution of genetic factors to schizophrenia is well
established because recent studies have identified a number of
strong candidate genes. However, the pathophysiology of
schizophrenia has not been totally elucidated yet. Alternative
pre-mRNA splicing increases proteomic diversity and
provides a potential mechanism underlying both phenotypic
diversity and susceptibility to genetic disorders in human
populations. To identify gene/pathway dysregulation
underpinning the neurobiological defects associated with
schizophrenia, we compared the transcriptomes of the
lymphoblastoid cell lines (LCLs) derived from 30
schizophrenic patients and 30 healthy controls. LCLs were
adopted to avoid the confounding factors related to the
postmortem brain such as agonal-pH factors, long-term
medication, and cause of death. We used the Affymetrix
GeneChip Human Exon 1.0 ST Array, which has 1.4 million
probe sets covering over one million known and predicted
human exons. In the gene level analysis with relaxed
parameters (p≤0.05, without multiple testing correction), 11
genes of schizophrenia group significantly changed ≥1.5-fold
or ≤0.67-fold compared to control group. In order to validate
the aforementioned finding, we conducted quantitative
real-time PCR using TaqMan Gene Expression Assays.
Moreover, we are going to combine the genotype data of the
same samples using the Genome-Wide Human SNP Array 5.0
to investigate whether single nucleotide polymorphisms
(SNPs) or copy number variations (CNVs) influence both
gene expression and alternative splicing (AS). The exon level
analysis and correlation analysis between SNPs/CNVs and
expression/AS is now on going.

210 LARGE SCALE RE-SEQUENCING OF THE
PSYCHOSIS SUSCEPTIBILITY GENE ZNF804A IN
SCHIZOPHRENIA
S. Dwyer* (1), M. Owen (1), N. Craddock (1), H. Williams
(1), M. O'Donovan (1)
1. Cardiff University
* dwyersl@cf.ac.uk
Recently, we undertook a GWAS of 479 UK schizophrenia
cases and 3000 controls (O'Donovan et al. 2008), with the
strongest 12 GWAS findings (P

212 MCHR1 SHOWS ASSOCIATION WITH
SCHIZOPHRENIA, AND POSSIBLY TREATMENT
RESPONSE AMONG DANISH CHRONIC
SCHIZOPHRENIA PATIENTS
A. Hedemand* (1), D. Demontis (1), M. Nyegaard (1), J.
Christensen (1), J. Severinsen (1), T. Hansen (2), T. Werge
(2), O. Mors (3), A. Børglum (1)
1. Institute of Human Genetics, Aarhus University, DK-8000
Århus C, Denmark 2. Research Institute of Biological
Psychiatry, Mental Health Centre Sct. Hans, Copenhagen
University Hospital, Roskilde, Denmark 3. Centre for
Psychiatric Research, Aarhus University Hospital, DK-8240
Risskov, Denmark
* anneh@humgen.au.dk
The gene MCHR1 is located on chromosome 22q13.2 and has
previously been associated with schizophrenia (SZ) in a study
of cases and controls from the Faeroe Islands and Scotland.
Here we report support of association between MCHR1 and
SZ based on analyses of a larger sample and increased number
of SNPs than used in the previous study. We analyzed a
case-control sample from Denmark consisting of 390 patients
with SZ and 814 control individuals, genotyped with 16
tag-SNPs. We performed gender-specific analysis as well as
analysis of association with antipsychotic treatment. We found
significant associations of independent SNPs in the proximal
region of GPR24 with SZ. The associations seemed to be
gender specific, coming from the males, and could be related
to medical treatment response. After correction for multiple
testing a single SNP remained significant (P=0.003), in the
association analysis of the males. A gene-wide p-value of
0.006 was obtained after correction for multiple testing. The
results suggest that MCHR1 may influence SZ susceptibility
in the Danish population and may possibly be involved in
treatment response among SZ patients.
213 UBIQUITIN PROTEASOME SYSTEM GENE
EXPRESSION CORRELATES FOR POSITIVE AND
NEGATIVE SYMPTOMS IN PSYCHOSIS
C. Bousman* (1), E. Tatro (1), G. Chana (1), S. Glatt (2), S.
Chandler (1), T. May (1), J. Lohr (1), W. Kremen (1), M.
Tsuang (1), I. Everall (1)
1. UCSD 2. SUNY Upstate Medical University
* cbousman@ucsd.edu
Several gene expression studies have identified genes in the
ubiquitin proteasome system (UPS) pathway as putative
biomarkers in psychotic disorders (e.g. schizophrenia).
However, to date an in-depth examination of the UPS pathway
in the context of psychosis has not been conducted. The
purpose of this study was to explore blood-based expression
correlates of 43 well characterized genes that operate within
the UPS pathway among a sample of 19 psychotic patients
diagnosed with schizophrenia (n = 13) or bipolar disorder (n =
6). Specifically, we sought to estimate the association of each
gene’s expression with clinical scores on the scales for the
assessment of positive and negative symptoms (SAPS-SANS).
Pearson’s partial correlations, adjusting for gender, ethnicity,
age, education, medication, smoking, and past six-month
substance use, were performed between each of the selected
UPS genes and both scales. SAPS results revealed significant
positive associations (Bonferroni p < 0.05) for two ubiquitin
conjugation genes (i.e. UBE2K, SIAH2) and a negative
association with one deubiquitination gene (i.e. USP2). No
gene expression levels were significantly associated with
scores on the SANS after multiple testing correction, albeit a
positive trend was observed for UBE2K. Findings suggest
that the UPS pathway, specifically ubiquitin conjugation and
deubiquitination may point to a possible underlying biological
mechanisms by which the severity of positive but not negative
symptoms clinically manifest.

214 CHRONIC RESTRAINT STRESS RESULTS IN
DIFFERENTIAL EXPRESSION OF SPLICE VARIANTS
OF THE SCHIZOPHRENIA AND BIPOLAR
DISORDER ASSOCIATED BRD1 GENE IN RAT
HIPPOCAMPUS
J. Christensen* (1), T. Fryland (1), B. Elfving (2), M.
Nyegaard (1), T. Corydon (1), A. Nielsen (1), O. Mors (2), G.
Wegener (2), A. Børglum (1)
1. Department of Human Genetics, Aarhus University,
Denmark 2. Centre for Psychiatric Research, Aarhus
University Hospital, Risskov, Denmark
* jhc@humgen.au.dk
Recent evidence has implicated the bromodomain containing 1
gene (BRD1) with brain development and susceptibility to
schizophrenia (SZ) and bipolar affective disorder (BD). The
Brd1 protein has been identified in the MOZ/MORF complex
responsible for H3 histone acetylation. Although indicating a
role of Brd1 in transcriptional regulation much remains to be
clarified with regard to its function and regulation. The aim of
the present study was to investigate the regulation and splicing
of the Brd1 gene in rats subjected to chronic restraint stress
(CRS). Male Sprague-Dawley rats (n=36) were subjected to
either half an hour or 6 hours of CRS once a day for 21 days,
or no CRS (controls). Relative transcript levels of the long
exon 7 splice variant of Brd1, total Brd1, and Mchr1 were
determined by quantitative RT-PCR on hippocampus RNA
using two stably expressed genes for normalization. We found
a significant 2-fold upregulation of the long splice variant of
Brd1 in both groups of CRS rats compared to controls. The
transcript levels of total Brd1 was not changed during CRS
indicating an equivalent downregulation of any other splice
variants. The amount of the Mchr1 transcript, another gene
associated with SZ, was unchanged. In conclusion, we
demonstrate that CRS in rats results in differential expression
of splice variants of the Brd1 gene in the hippocampus. As
CRS causes decreased hippocampal neurogenesis and adaptive
structural plasticity, it is tempting to speculate that regulation
and splicing of the Brd1 gene plays an important role in these
processes that are well-known to be disturbed in SZ and BD.
215 IDENTIFICATION OF NOVEL CANDIDATE
GENES FOR TREATMENT RESPONSE TO
RISPERIDONE AND SUSCEPTIBILITY FOR
SCHIZOPHRENIA
M. Ikeda* (1, 2), Y. Tomita (3), A. Mouri (4), M. Koga (5, 6),
T. Okochi (2), R. Yoshimura (7), Y. Yamanouchi (2), Y.
Kinoshita (2), R. Hashimoto (6, 8), H. Williams (1), M.
Takeda (8), J. Nakamura (7), T. Nabeshima (4), M. Owen (1),
M. O'Donovan (1), H. Honda (3), T. Arinami (5, 6), N. Ozaki
(3, 6), N. Iwata (2, 6)
1. Cardiff University 2. Fujita Health University 3. Nagoya
University 4. Meijo University 5. University of Tsukuba
6. CREST 7. University of Occupational and Environmental
Health 8. Osaka University
* ikedam@cardiff.ac.uk
Background: Pharmacogenomic approaches based upon
genome-wide sets of single nucleotide polymorphisms (SNPs)
are now feasible, and offer the potential to uncover variants
that influence drug response. Methods: To detect potential
predictor gene variants for risperidone response in
schizophrenic subjects, we performed a convergent analysis
based upon (1) a genome-wide (100K SNP) SNP
pharmacogenetic study of risperidone response and (2) a
global transcriptome study of genes whose mRNA levels are
influenced by risperidone exposure in mouse prefrontal cortex.
Results: Fourteen genes were highlighted as of potential
relevance to risperidone activity in both studies; ATP2B2,
HS3ST2, UNC5C, BAG3,PDE7B, PAICS, PTGFRN, NR3C2,
ZBTB20, ST6GAL2, PIP5K1B, EPHA6, KCNH5 and AJAP1.
The SNPs related to these genes that were associated in the
pharmacogenetic study were further assessed for evidence for
association with schizophrenia in up to 3 case control series
comprising 1564 cases and 3862 controls in total (Japanese
(JPN) 1st and 2nd samples and UK sample). Of 14 SNPs
tested, one (rs9389370) in PDE7B showed significant
evidence for association with schizophrenia in a discovery
sample (Pallele=0.026 in JPN1st, 2-tailed). This finding
replicated in a joint analysis of two independent case-control
samples (PJPN2nd+UK=0.008, 1-tailed, uncorrected) and in
all combined datasets (Pall=0.0014, 2-tailed, uncorrected and
Pall=0.018, 2-tailed, Bonferroni correction). Conclusions: We
identify novel candidate genes for treatment response to
risperidone, and provide evidence that one of these
additionally may confer susceptibility to schizophrenia.
Specifically, PDE7B is an attractive candidate gene though
evidence from integrated methodology including
pharmacogenomics, pharmacotranscriptomic, and case-control
association approaches.

216 NPAS3 AND SOX FAMILY GENES:
TRANSCRIPTIONAL CONTROL OF NEURONAL
PROLIFERATION AND DIFFERENTIATION AND ITS
RELATION TO PSYCHIATRIC ILLNESS
L. Sha* (1), M. Malloy (2), W. Muir (3), D. Blackwod (3), B.
Pickard (4)
1. University of Edinburgh, Western General Hospital,
Einburgh, EH4 2XU, UK 2. University of Edinburgh,
Einburgh, EH4 2XU, UK 3. Division of Psychiatry, University
of Edinburgh, EH10 5HF, UK 4. University of Strathclyde,
Glasgow, G4 0NR, UK
* s0676701@sms.ed.ac.uk
Neuronal basic helix-loop-helix PAS domain transcription
factor 3, NPAS3, has been implicated in susceptibility to both
schizophrenia and bipolar disorder by cytogenetics,
genome-wide association and a knockout mouse model.
Studying the established role of NPAS3 in adult hippocampal
neurogenesis may provide a biological mechanism for the link
between neurogenesis dysfunction and psychiatric disorders.
SOX family transcription factors are also known to play a role
in neural progenitor proliferation and differentiation. To
explore the transcriptional network controlled by these genes
we used overexpression in HEK293 cells coupled with
microarray analysis to identify target genes and pathways.
Four key observations were made. Firstly, NPAS3 strongly
activates VGF, a gene that links defective neurogenesis with
depression in a mouse model. Secondly, NPAS3 regulates
several SOX genes, including SOX11, and displays a similar
target activation profile to SOX5/SOX6. Thirdly, NPAS3, like
NPAS2, is implicated in energy homeostasis by repressing
genes encoding the majority of enzymes involved in
glycolysis. Lastly, SOX11, which plays a key role during
neuronal differentiation activates expression of a cluster of
histone genes on chromosome 6 that lie within the principal
region associated with schizophrenia in recent genome-wide
association studies. Q-PCR confirmation studies will be
presented along with immunofluorescence findings of the
NPAS3, SOX11 and target proteins in the hippocampus. We
will also detail ongoing work attempting to place these genes
within the time-course of neural prescursor cell differentiation.
These data begin to unravel the component pathways of
neurogenesis and how they might impact on the aetiological
processes of psychiatric illness.
217 ANALYSIS OF AN ASSOCIATION BETWEEN THE
DRD3, TPH2 AND HTR-2A GENES POLYMORPHISM
AND SCHIZOPHRENIA (SCHZ) IN MALAYSIAN
INDIVIDUALS
S. Tee*, T. Chow, H. Loh, P. Tang
* teesf@utar.edu.my
Molecular components of the dopaminergic and serotoninergic
pathways may play an important role in the pathophysiology
of schizophrenia. The roles of the dopaminergic and
serotoninergic systems have been implicated in the etiology of
schizophrenia (SCHZ) and other behavioral disorders. In this
study, we investigated the relationship of the single nucleotide
polymorphisms (SNPs) of Ser9Gly DRD3, rs-1438G/A
5-HTR2A and intronic rs1386494 TPH2 with Malaysia
cases-control. A total of 201 patients with SCHZ and 111
healthy controls were investigated. PCR-RFLP was performed
to genotype these three SNPs and deviation from Hardy
Weinberg Equilibrium was determined. Allele and genotype
distributions of rs-1438G/A 5-HTR2A showed a significant
difference for cases and controls. However, no associations
were found between the Ser9Gly DRD3 and intronic
rs1386494 TPH2 with SCHZ while rs-1438G/A 5-HTR2A
could be a susceptible gene for SCHZ based our preliminary
results. We believe that further studied are required to
examine the relationship between other dopamine and
serotonin-related genes and the behavioral phenotypes of
SCHZ in the Malaysia individuals.

218 CYTOGENETIC DAMAGE IN SCHIZOPHRENIA
POPULATION, TAMIL NADU, INDIA.
V. Balachandar* (1)
1. Human Genetics Laboratory, Bharathiar UNiversity,
Coimbatore, Tamil Nadu, India
*geneticbala@yahoo.co.in
Schizophrenia is a relatively common debilitating, chronic,
psychotic disorder. The focal aim of the present investigation
was to identify the foremost chromosomal aberrations (CA)
like deletion, translocation, inversion and mosaic in
schizophrenic subjects of Tamilnadu, Southern India. In the
present investigation 54 schizophrenia patients from 15 to
58yrs of age and equal number of normal,
Healthy controls in the same age wise manner were selected.
After signing a consent form, both cases (experimentals and
controls) provided a blood sample (5 ml) to establish cell
culture. In 41 patients random numerical and structural
aberrations were identified. Structural aberrations
predominated, consisted of deletions, translocation, inversion
and mosaicism of various chromosomes. Our study has
detected 1, 7, 9, 11, 13, 21, and X suggested that these
chromosomal scratches are prevalent in schizophrenics. In
comparison with experimental subjects, the control subjects
exhibited very low levels of major CA (P

220 DENSE ASSOCIATION MAPPING OF
DIHYDROPYRIMIDINASE-LIKE 2 (DPYSL2) GENE IN
SUSCEPTIBILITY TO SCHIZOPHRENIA IN THE
JAPANESE POPULATION
T. Koide*, B. Aleksic, I. Kushima, Y. Nakamura, Y. Ito, T.
Inada, N. Iwata, N. Ozaki
*t-koide@med.nagoya-u.ac.jp
Dihydropyrimidinase-like 2 (DPYSL2), also known as
collapsin response mediator protein 2 (CRMP2), mediates the
intracellular response to collapsin, a repulsive extracellular
guidance cue or axonal outgrowth. DPYSL2 was reported as a
schizophrenia susceptibility gene by Nakata et al, and several
independent association studies have replicated this
association signal. However, the results of replication studies
using smaller sets of markers have been inconsistent.
Therefore, in order to address this issue, we performed dense
association mapping of DPYSL2 in a Japanese population.
SNP Tagging criteria were based on minor allele frequency
(>10 %) and correlation coefficient between loci (>0.8) as
reported in HAPMAP database.After genotyping of 23 SNPs,
we identified 2 association signals in a statistical analysis
(rs2585458; allelic P value: 0.048, rs4733048; genotypic P
value: 0.02 and allelic P value: 0.01, before multiple
comparison correction). In order to confirm this finding, we
are typing independent cohorts for these 2.Our data provided
evidence that DPYSL2 might elevate the risk for
schizophrenia in the Japanese population. However,
replicating the finding using larger sample size would be
necessary for conclusive results. We concluded that the results
were suggestive of an association with schizophrenia at this
locus, but that they could not be considered conclusive
without further replications.
221 FURTHER EVIDENCE FOR ASSOCIATION OF
WNT PATHWAY RELATED GENES WITH
SCHIZOPHRENIA
I. Kushima* (1), B. Aleksic (1), Y. Ito (1), Y. Nakamura (1),
N. Iwata (2), N. Ozaki (1)
1.Nagoya University Department of Psychiatry 2. Fujita health
University Department of Psychiatry
*kushima.itaru@a.mbox.nagoya-u.ac.jp
Abnormalities in brain development, such as faulty neuronal
migration, altered spatial neuronal arrangement and the
absence of significant gliosis, have been reported in
schizophrenia. Recent advances in the understanding of genes
that regulate brain development offer insights into the
mechanism that underlie such developmental brain changes.
One such genetic components involves the Wnt signaling
which is central to normal brain development and which
mediates cell adhesion, proliferation and gene transcription.
Both DKK1 and KREMEN1 are on the Wnt pathway. DKK1
gene encodes a protein that is a member of the dickkopf
family. It is a secreted protein with two cysteine rich regions
and is involved in embryonic development through its
inhibition of the Wnt signaling. KREMEN1 encodes a
high-affinity DKK1 transmembrane receptor that functionally
cooperates with DKK1 to block Wnt signaling. KREMEN1 is
located in chromosome 22 q12.1, a region implicated in
several schizophrenia linkage studies.The aim of the current
study was to examine the association of KREMEN1 and
DKK1 and schizophrenia in a Japanese population. We
genotyped 16 genetic variants within the two genes and
examined their association with schizophrenia. Our samples
consisted of 1573 patients with schizophrenia and 1580
healthy controls divided into two sets. All subjects were of
Japanese descent. One variant in KREMEN1, rs713526 was
significantly associated with schizophrenia. We replicated this
association at the second sample sets.

222 AN ASSOCIATION STUDY OF TAGGING SNPS OF
RAB23 AND SCHIZOPHRENIA IN JAPANESE
POPULATION
B. Aleksic* (1), I. Kushima (1), Y. Ito (1), Y. Nakamura (1),
T. Inada (1), N. Iwata (1), N. Ozaki (1)
1. Department of Psychiatry, Graduate School of Medicine,
Nagoya University, Japan
*branko@med.nagoya-u.ac.jp
RAB23, member RAS oncogene family, is a human gene. The
protein encoded by this gene belongs to the small GTPase
superfamily, Rab family. It is involved in small GTPase
mediated signal transduction and intracellular protein
transportation. Alternative splicing occurs at this locus and
two transcript variants encoding the same protein have been
identified. In the brain, RAB23 is found predominantly in cell
bodies of neurons. This gene is attractive functional candidate
gene for schizophrenia, and so far there was no association
study focused on this locus. Therefore, the goal of this study
was to assess the influence of genetic factors related to this
locus on schizophrenia from point of common disease
common variant hypothesis. Total of 11 SNPs were selected
for comprehensive coverage of RAB23 locus. Tagging criteria
are based on minor allele frequency (>5 %) and correlation
coefficient between loci (>0.8) as reported in HAPMAP
database. Our sample consisted of 754 schizophrenic patients
and 783 healthy controls. We detected 3 association signals in
3’ region of the RAB23.Our data provided evidence that
common SNP within RAB23 locus might elevate the risk for
schizophrenia in the Japanese population. However,
replicating the finding using larger sample size would be
necessary for conclusive results. We concluded that the results
were suggestive of an association with schizophrenia at this
locus, but that they could not be considered conclusive
without further replications.
223 TAG-SNP BASED ASSOCIATION STUDY OF 109
CANDIDATE GENES FOR SCHIZOPHRENIA
SELECTED USING AN EVIDENCE-BASED
PRIORITIZATION ALGORITHM
A. Fanous* (1), Z. Zhao (2), B. Webb (3), E. van den Oord
(3), B. Maher (3), S. Bergen (3), R. Amdur (1), F. O'Neill (4),
D. Walsh (5), B. Riley (3), K. Kendler (3)
1. Washington VA Medical Center 2. Vanderbilt University
3. Virginia Commonwealth University 4. Queen's University,
Belfast 5. Health Research Board, Dublin
*ahfanous@vcu.edu
Integrating evidence from multiple domains may be useful in
prioritizing genes for subsequent testing. We ranked all
known genes under several linkage peaks in the Irish Study of
High-Density Schizophrenia Families using three different
evidence domains; 1) a meta-analysis of microarray gene
expression results using the Stanley Brain collection, 2) a
schizophrenia protein-protein interaction network, and 3)
systematic literature searching. Each gene was assigned a
domain specific p-value and ranked after evaluating the
evidence within each domain. For Protein-Protein Interaction,
the steps from the schizophrenia susceptibility genes a)
DTNBP1, b) NRG1, and c) Akt1 in Protein-Protein
Interaction databases were determined, respectively. For
Literature Searches, Pubmed was systematically searched
using all genes with 40 schizophrenia-related search terms.
For a final ranking of these genes, we summed the -log10 of
their P-values on each of these five variables (or Q-values in
the case of Gene Expression). In addition, any gene with Gene
Ontology terms that included “nervous system development”
or “brain development” was also selected (n=65).
Approximately 3000 SNPs from a custom Illumina iSelect
genotyping array using the Infinium assay were allocated to
evaluate selected genes. After assigning all LD tagging SNPs
in ranked genes, these, and the top 44 genes were investigated
using 2,849 SNPs. No individual SNPs were significant after
correction for multiple testing. However, a number of genes
contained clusters of SNPs with p

224 GENOME-WIDE ASSOCIATION STUDY OF
SCHIZOPHRENIA IN A SWEDISH
POPULATION-BASED SAMPLE
Y. Liu* (1), C. Hultman (2), P. Lichtenstein (2), P. Sklar (3),
P. Sullivan (1)
1. The University North Carolina at Chapel Hill, Department
of Genetics 2. Karolinska Institute 3. Massachusetts General
Hospital
*youfang@email.unc.edu
Schizophrenia is a complex disease with multiple genes and
environmental exposures likely involved. This study includes
three sets of Swedish cases and controls totaling 1097 cases
and 1303 controls with all individuals selected from
population-based registries. Cases were hospitalized at least
twice with a discharge diagnosis of schizophrenia or
schizoaffective disorder (we have previously shown that this
definition of illness corresponds closely to standard
definitions). Controls were required never to have been
hospitalized for a psychotic illness. GWAS genotyping was
conducted at the Broad Institute using Affymatrix 5.0 and 6.0
arrays. To ensure data quality, harsh quality control was
performed: SNPs with missing rate > 0.01, MAF < 0.05 or
HWE deviations were excluded. Subjects with missing rate >
0.01, 2nd or 1st degree relationship with other individuals, and
outlying empirical ancestries were removed. Imputation was
accomplished by MACH for each data set. GWAS was
performed by ProbABEL using logistic regression.
Fixed-effects meta-analysis was applied using a weighted
z-score method and its distribution was checked for inflation
by (lambda = 1.00). Although no marker reached
genome-wide significance, the top two genes were interesting.
MAGI2 (Pmin= 1.3e-6) is a possible scaffold molecule at
synaptic junctions and may assemble neurotransmitter
receptors and cell adhesion proteins and regulate
activin-mediated signaling in neuronal cells. The second gene,
GABRB3 (Pmin=3.7e-6), is a ligand-gated ionic channel
family and encodes a subunit of the receptor for
gamma-aminobutyric acid which is the major inhibitory
transmitter of the nervous system, and a prior candidate gene
for schizophrenia.
225 EXTENDED HAPLOTYPE SHARING IN
SCHIZOPHRENIA
Y. Liu* (1), K. Wilhelmsen (1), C. Hultman (2), P.
Lichtenstein (2), P. Sklar (3), P. Sullivan (1)
1. The University North Carolina at Chapel Hill, Department
of Genetics 2. Karolinska Institutet 3. Massachusetts General
Hospital
*youfang@email.unc.edu
Recently, a long segment with high LD containing hundreds
SNPs and multiple genes in the MHC region on chromosome
6p21.3-22.1 was identified by association analyses in
European schizophrenia studies. Thus, long haplotype or long
DNA segment based association methodology is worthy of
exploration for relevance to schizophrenia. Haplotype sharing
methods have been shown by simulation to achieve higher
power than single maker analysis. However, most current
haplotype sharing methods can only handle short haplotypes.
CHAT (Convergent Haplotype Association Tagging), a new
long haplotype sharing method developed by Dr Kirk
Wilhelmsen (unpublished), implements a computationally
intensive heuristic algorithm that identifies long shared
haplotypes for which subsets of the population are likely to
have inherited from a recent common ancestor. CHAT is
designed to detect mutations of moderate penetrance and is
resistant to the confounding effects of population substructure
and allelic and locus heterogeneity. We applied CHAT to an
unpublished schizophrenia case-control data set from a
population based sample of 538 cases and 904 controls
genotyped at the Broad Institute using Affymatrix 6.0 arrays.
Harsh quality control was performed before analysis. Two
regions were identified by CHAT. Both are rare variants
which were not detected by single marker analysis - a 350 Kb
region located on chromosome 3 containing one possible gene
and a 3.8 Mb region located on chromosome 15 containing
more than 20 genes involved in FGFR signaling pathway and
lipid and lipoprotein metabolism – although the MHC region
was not detected.

226 ASSOCIATION BETWEEN COMT GENE
MET158VAL POLYMORPHISM AND
SCHIZOPHRENIA
H. Loh* (1), S. Tee (2), T. Chow (3), P. Tang (4)
1. Universiti Tunku Abdul Rahman
*hcloh@utar.edu.my
Catechol-O-methyltransferase (COMT) is an enzyme involved
in the degradation of the neurotransmitter dopamine (DA). A
single nucleotide polymorphism (SNP) within the
humanCOMT gene dramatically affects the activity of the
enzyme and as a result, directly influences DA availability in
the brain. In this study, we examined the relationship of the
single nucleotide polymorphism (SNP) between the COMT
Met158Val polymorphism in 123 healthy individuals and 143
schizophrenic patients (MINI criteria) in Malaysia.
PCR-RFLP was performed to genotype the COMT Met158Val
SNP. Allele and genotype distributions showed a significant
difference between Malaysia cases and controls. Both of the
groups are out of Hardy -Weinberg equilibrium for the
analyzed genetic variability. Further studies are required to
examine the relationship between dopamine-related genes and
the behavioral phenotypes of schizophrenia in the Malaysia
population.
227 FIBROBLAST GROWTH FACTORS AND BRAIN
VOLUME IN SCHIZOPHRENIA PATIENTS AND
HEALTHY CONTROLS
A. Terwisscha van Scheltinga* (1), S. Bakker (1), N. van
Haren (1), H. Hulshoff Pol (1), W. Cahn (1), R. Ophoff (1), R.
Kahn (1)
1. UMC Utrecht
*aterwiss@umcutrecht.nl
Background: There is convincing evidence for an involvement
of fibroblast growth factors (FGFs) in schizophrenia 1. FGFs
regulate growth, maintenance and repair of neuronal tissue.
This makes the genes in the FGF system plausible candidate
genes for the smaller brain volume seen in schizophrenia
patients and their relatives relative to control subjects. We use
total brain volume as an endophenotype of schizophrenia,
since it has a 90% heritability, can be reliably measured,
cosegregates with illness in families and is relatively
independent of clinical state 2. Method: Using online genomic
databases 915 SNPs in 22 FGFs, 5 FGF receptors and 56
interacting genes were selected and genotyped using the
Illumina HumanHap550 beadchip. A 1.5T MRI scan of the
brain was acquired for 169 schizophrenia cases and 159
healthy controls. Total brain volume was estimated and
corrected for age, sex and intracranial volume. A linear
regression analysis was performed, using disease status as an
independent variable. Results: After correction for 83 genes 1
SNP in fibroblast growth factor receptor substrate 2 (FRS2)
showed suggestive association with total brain volume
(corrected p = 0.056) both in patients and controls, explaining
3% of the variation in total brain volume. Discussion: This
SNP is associated with the normal variation in total brain
volume rather than with the disease specific decline in total
brain volume.

228 IDENTIFICATION OF THE SUBCELLULAR
LOCALIZATION DISC1 ISOFORMS AND THE
IMPACT OF A NOVEL DISC1 ISOFORM, DISC1-ESV,
IN SCHIZOPHRENIA
C. Wen* (1), C. Liu (1), Y. Liu (2), H. Hwu (1)
1. Department of Psychiatry, National Taiwan University
Hospital and National Taiwan University College of
Medicine, Taipei, Taiwan 2. Division of Mental Health and
Substance Abuse Research, National Health Research
Institutes, Miaoli, Taiwan
*f90445111@ntu.edu.tw
Schizophrenia is one of the neuropsychiatry disorders. Genetic
studies have indicated that many genes are associated with
schizophrenia. Disrupted-in-schizophrenia 1 (DISC1) was first
identified in a large Scottish family which had been reported
as one of the risk gene involved in the pathogenesis of
schizophrenia. Previous studies indicated that endogenous
DISC1 could locate in nucleus, cytoplasm, centrosome and
mitochondria, and DISC1-L form could locate in nucleus and
cytoplasm. The functions of DISC1 might involve with neurite
outgrowth and cell cycle regulation; however, the detail
functions of DISC1 were still unclear. DISC1 included at least
four isoforms but, few of studies described the functions of all
DISC1 isoforms. In this paper, we wanted to identify the
functions and cellular distributions of all DISC1 isoforms. It is
the first time to study the difference between all DISC1
isoforms. We cloned DISC1 isoforms expression constructs
included DISC1-L, DISC1-Lv, DISC1-S and a novel isoform,
DISC1-Esv, from human hippocampus but we failed to clone
DISC1-Es form. Immunofluorenscence assay indicated that
majority of DISC1-L and Lv form could be observed in
cytoplasm and DISC1-S could be detected both in nucleus and
cytoplasm and DISC1-Esv also could be recognized both in
nucleus and cytoplasm, but DISC1-Esv with dense stained in
nucleus. The subcellular localization of DISC1-L, Lv and Esv
could change after retinoic acid treatment. Furthermore, the
RNA expression level of DISC1-Esv in schizophrenia patient
was higher than that in control. Taken together, DISC1-L Lv
and Esv might involve in neurite outgrowth regulation, and
DISC1-Esv might be an candidate risk protein in Taiwanese
schizophrenia population.
229 NO ASSOCIATION OF THE SEROTONIN
TRANSPORTER POLYMORPHISMS 5-HTTLPR AND
RS25531 WITH SCHIZOPHRENIA OR
NEUROCOGNITION
T. Konneker* (1), J. Crowley (1), C. Quackenbush (1), R.
Keefe (2), D. Perkins (3), T. Stroup (3), J. Lieberman (4), E.
van den Oord (5), P. Sullivan (6)
1. Department of Genetics, University of North Carolina at
Chapel Hill 2. Department of Psychiatry, Duke University
3. Department of Psychiatry, University of North Carolina at
Chapel Hill 4. Department of Psychiatry, Columbia University
5. Department of Pharmacology, Virginia Commonwealth
University 6. Department of Genetics, University of North
Carolina at Chapel Hill; Department of Medical Epidemiology
& Biostatistics, Karolinska Institutet, Stockholm, Sweden
*kneeker@med.unc.edu
The 5-HTTLPR is a 44 base pair insertion-deletion
polymorphism in the promoter region of the serotonin
transporter (SLC6A4), and contributes to the regulation of the
expression of SLC6A4. The serotonin transporter is a
membrane bound protein which transports serotonin from
synapses into pre-synaptic neurons. The 5-HTTLPR has been
heavily studied in relation to many psychiatric diseases,
endophenotypes, and drug response phenotypes. A single
nucleotide polymorphism rs25531 (A/G) within the
polymorphic 5-HTTLPR has been shown to alter expression
of SLC6A4 . Many prior studies have thus incorrectly
considered this triallelic polymorphism as biallelic (i.e.,
5-HTTLPR*LA, LG, and S as opposed to 5-HTTLPR*L or S).
In light of this discovery and the prevalence of rs25531 in
certain ancestry groups, it is possible that previous studies
may have been confounded by the previously unknown
variant. Therefore, we tested 5-HTTLPR and rs25531 for
association with chronic schizophrenia, cognitive phenotypes
related to schizophrenia, and symptom status in a sample of
728 cases and 724 controls from the CATIE sample. We
found no significant association of the 5-HTTLPR/rs25531
composite genotype with the diagnosis of schizophrenia
(p=0.72), an omnibus measure of neurocognition (p=0.21) or
with working memory (p=0.32) at study baseline. Similarly,
there was no association with PANSS positive (p=0.67) or
negative symptoms (p=0.46) at study baseline (covariates age,
sex, and 7 principal components). In conclusion, we were
unable to identify association of the 5-HTTLPR/ rs25531 with
schizophrenia, neurocognition, or core psychotic symptoms –
even at levels of significance unadjusted for multiple
comparisons.

230 GENETIC MARKERS FOR SUICIDE RISK IN
SCHIZOPHRENIA
E. Olsson* (1), D. Sudic (2), H. Druid (3), M. Schalling (2),
U. Ösby (1)
1. Department of Clinical Neuroscience, Karolinska Institutet,
Stockholm, Sweden; Department of Psychiatry, Danderyd
University Hospital, Stockholm, Sweden 2. Department of
Molecular Medicine and Surgery, Karolinska Institutet,
Stockholm, Sweden 3. Department of Oncology-Pathology,
Karolinska Institutet, Stockholm, Sweden
*eric.olsson@sll.se
Around 5% of patients with schizophrenia will die from
suicide. Improved prediction of increased suicide risk is of
great importance in order to improve prognosis in
schizophrenia. Molecular genetic association studies of suicide
risk, also in schizophrenia, have focused on genes related to
the serotonin system. There are several promising findings but
also some contradictory results. This may be due to limitations
of association studies, too small samples, diagnostic
heterogeneity, and suicide attempt as phenotype rather than
suicide per se. The purpose of this study is to identify genetic
risk markers for suicide in schizophrenia. We use genetic
association, comparing schizophrenic patients who have died
from suicide with living schizophrenic patients, and also with
a population-based control group. By linkage of diagnosis
from the Patient Register with the cause of death from the
Swedish Forensic database, 351 cases from three Counties in
Sweden have been identified. The cases have a clinical
schizophrenia diagnosis, have suicide as the certain, probable
or possible cause of death and there is tissue available from
the forensic autopsy. The control groups consist of patients
with schizophrenia, and blood donor population controls from
Stockholm County. This poster will describe the cases and the
structure of the project.We will initially analyze SNPs based
on previous studies in the genes TPH1, TPH2, 5-HTT,
MAO-A, 5HT2A, all involved in the serotonin pathway. This
study will in a favorable way address previous problems with
identifying genetic markers for increased suicide risk in
schizophrenia.
231 PROTEOMIC ANALYSIS OF THE
LYMPHOBLASTOID CELL LINE IN THE JAPANESE
SCHIZOPHRENIC PATIENTS
A. Yoshimi* (1), T. Nagai (1), S. Yamada (2), R. Ishihara (3),
M. Ohashi (2), Y. Ito (3), Y. Noda (2), K. Yamada (1), N.
Ozaki (3)
1. Department of Neuropsychopharmacology and Hospital
Pharmacy, Nagoya University Graduate School of Medicine
2. Division of Clinical Sciences and
Neuropsychopharmacology, Graduate School of
Pharmaceutical Sciences, Meijo University 3. Department of
Psychiatry, Nagoya University Graduate School of Medicine
*akira-yoshimi@med.nagoya-u.ac.jp
Schizophrenia is a chronic and disabling mental disorder with
a lifetime prevalence of approximately 1% of the global
population. There is no validated method based on the
pathophysiology for diagnosis of the disease although a
number of studies have shown several convincing candidate
genes or molecules. Proteomic analyses have many
advantages compared to gene expression analyses since they
can provide further understandings for pathophysiology of
disease and the molecular biology based diagnostic tools. To
explore the biomarkers of schizophrenia, we performed the
florescence two-dimensional differential gel electrophoresis
(2D–DIGE) analysis of lymphoblastoid cell line from 29
schizophrenia and 29 control subjects. Differentially expressed
proteins were subsequently identified by LC-MS/MS. A
2D-DIGE analysis revealed that 1103±11.7 and 1103±13.3
unique spots were identified in the schizophrenia and control
group, respectively. No differences were observed between
two groups in the total number of protein spots, and more than
95% of all spots were matched to the reference gel. Changes
in the relative abundance of 20 protein spots were identified in
the schizophrenia compared to the control group. Seven spots
exhibited an increase in the schizophrenia whereas 13 protein
spots were decreased (Student’s t-test, p

232 ANALYSIS OF GENE EXPRESSION IN
DORSOLATERAL PREFRONTAL CORTEX OF
SCHIZOPHRENICS AND CONTROLS
E. Shen* (1), A. Guillozet-Bongaarts (1), T. Hyde (2), B.
Swanson (1), L. Kuan (1), J. Royall (1), J. Hohmann (1), A.
Jones (1), J. Kleinman (2), H. Zeng (1)
1. Allen Institute for Brain Science 2. Clinical Brain Disorders
Branch, Genes Cognition and Psychosis Program, Intramural
Research Program, NIMH, NIH
*elaines@alleninstitute.org
A dataset of gene expression information using colorimetric in
situ hybridization (ISH) in postmortem human dorsolateral
prefrontal cortex (DLFPC) of schizophrenic (SCZ; n = 15) and
control subjects (n = 33) was generated for 60 genes
comprising SCZ candidate genes, cell-type markers and
cortical layer markers. An established high-throughput
process and platform was used to perform ISH on frozen
tissue that was sectioned, placed on slides and exposed to
cDNA probes specifically targeted to each of the 60 genes of
interest. Nissl stained reference sections were generated every
500 um. All Nissl and ISH slides were digitally scanned and
all QC-passed data images were made publicly available via
the Allen Institute’s data portal, www.brain-map.org.
Brodmann areas 9 and 46 were delineated on all nissl stained
sections. To characterize overall variability in DLPFC gene
expression patterns, as well as differences in gene expression
between SCZ and control subjects, a quantitative data analysis
strategy was developed that includes informatics-based
detection and analysis of four main ISH metrics: percentage
of total area labeled, number of expressing objects
(presumably cells) per mm2, object optical density (gene
expression intensity in cells), and integrated optical density.
Data profiles were generated by plotting each metric against
cortical depth. Our initial analyses demonstrated that: (1) data
profiles recapitulated gene expression patterns and (2) GRIK4
gene expression differed between SCZ and control groups.
Analysis of KIAA1576 indicated possible population
differences in expression patterns.
233 WHOLE GENOME SCAN ON SCHIZOPHRENIA
IN 2 ARAB ISRAELI SAMPLES
S. Lupoli* (1), P. Cozzi (2), A. Alkelai (3), A. Orro (2), F.
Torri (4), E. Salvi (5), C. Cosentino (5), V. Tieran (5), L.
Milanesi (2), B. Lerer (3), F. Macciardi (6)
1. INSPE, San Raffaele Scientific Institute, Milan, Italy;
University of Milan, Filarete Foundation, Milan, Italy
2. ITB, CNR, Milan, Italy 3. Hadassah–Hebrew University
Medical Center, Jerusalem, Israel 5. University of Milan,
Filarete Foundation, Milan, Italy 6. University of Milan,
Filarete Foundation, Milan, Italy; Department of Psychiatry
and Human Behavior, University of California, Irvine, CA,
USA
*sara.lupoli@hsr.it
Schizophrenia is a major public health problem with a 1%
incidence worldwide, a high suicide rate, and enormous
human and financial costs. It is widely considered to be a
genetically mediated neurodevelopmental disorder and
identification of potential candidate genes has accelerated in
recent years. Whole-genome association (WGA) studies have
identified multiple regions across the genome that are
promising candidates of modest effect for schizophrenia. For 2
Arab Israeli families with multiple cases of schizophrenia, we
have performed a WGA family study examining
approximately 370 000 markers (Illumina
HumanCNV370-Duo). Plink 1.06 was used for quality
control (QC) of genotype data, IBD (identity-by-descent)
similarity matrix for checking pedigree errors, Transmission
Disequilibrium Test (TDT) and permutations as correction
methods for the TDT. Preliminary analysis shows 34 SNPs
with p-value exceeding significance 10E-5 or less. Two SNPs
bypass a p-value of 4.00E-06; one maps in SLIT (slit
(Drosophila) homolog 1) gene and 1 in AHI1. Thirty-two
SNPs reach 1e-05. Among our best results we detected
associated SNPs in N-Methyl-D-Aspartate Receptor subunit
2B (GRIN2B), Nerve Growth Factor Receptor (NGFR), and
Glutamate Receptor Metabotropic 8 (GRM8), confirming
previous studies on schizophrenia. Most of our associated
genes are involved in neurodevelopment pathways.As recent
papers (1,2) support association between chromosomal
abnormalities and schizophrenia, analysis of Copy Number
Variation (CNV), structural variations within the human
genome, is on going on our datasets. 1 The International
Schizophrenia Consortium: Rare chromosomal deletions and
duplications increase risk of schizophrenia. Nature 455,
237-241, 2008. 2Terry Vrijenhoek et al.: Recurrent CNVs
Disrupt Three Candidate Genes in Schizophrenia Patients. The
American Journal of Human Genetics 83, 504–510, 2008.

234 NRG1 AND DTNBP1 ARE ASSOCIATED WITH
NON-DEFICIT SCHIZOPHRENIA AND SYMPTOM
SEVERITY IN A HUNGARIAN SAMPLE
J. Réthelyi* (1), S. Bakker (2), P. Polgár (1), P. Czobor (1), E.
Strengman (3), P. Pásztor (4), R. Kahn (2), I. Bitter (1)
1. Department of Psychiatry and Psychotherapy, Semmelweis
University, Budapest, Hungary 2. The Rudolf Magnus
Institute of Neuroscience, Department of Psychiatry,
University Medical Centre Utrecht, Utrecht, The Netherlands
3. Complex Genetics Section, Department of Biomedical
Genetics, University Medical Center Utrecht, Utrecht, The
Netherlands 4. Department of Psychiatry, St. John’s Hospital,
Budapest, Hungary
*rethelyi@psych.sote.hu
Association studies have yielded extensive, but frequently
contradictory data about the genetic risk factors of
schizophrenia. Clinical and genetic heterogeneity are possible
factors explaining the inconclusive findings. The objective of
this study was to test the association of commonly
incriminated candidate genes with two clinically divergent
subgroups, non-deficit (SZ-ND) and deficit-schizophrenia
(SZ-D), and with symptom severity. DNA samples from a
homogeneous sample of 280 schizophrenia patients and 230
healthy controls of Hungarian, Caucasian descent were
genotyped for polymorphisms in schizophrenia candidate
genes NRG1, DTNBP1, RGS4, G72/G30 and PIP5K2A.
Patients were divided into the diagnostic subgroups of SZ-ND
and SZ-D using the Schedule for Deficit Syndrome (SDS),
and assessed clinically by the Positive and Negative Symptom
Scale (PANSS). Polymorphisms in RGS4, G72/G30, and
PIP5K2A were neither associated with SZ-ND, nor SZ-D.
SNP8NRG241930 in NRG1 and rs1011313 in DTNBP1 were
associated with SZ-ND (p=0.04 and p=0.03, respectively).
SNP8NRG241930 showed association with the PANSS
cognitive and hostility/excitability factor, rs1011313 with the
negative factor and SDS total score, and rs10917670 in RGS4
was associated with the depression factor. Our data seem to
confirm previously reported association of NRG1 with
schizophrenia without prominent negative symptoms. It was
possible to detect association of small to medium effect sizes
between the investigated candidate genes and symptom
severity. Similar studies may unravel the possible connection
between genetic and clinical heterogeneity in schizophrenia.
235 SYSTEMATIC MUTATION SCREENING STUDY
FOR ANXA7 AND PPP3CB IN SCHIZOPHRENIA
C. Liu* (1), H. Hwu (1), U. Yang (2), P. Hsu (2), C. Fann (3),
Y. Liu (4), C. Wen (1), C. Chang (3)
1. Department of Psychiatry, National Taiwan University
Hospital, Taipei, Taiwan 2. Institute of Bioinformatics,
National YangMing University, Taipei, Taiwan 3. Institute of
Biomedical Science, Academia Sinica, Taipei, Taiwan 4.
Division of Mental Health and Substance Abuse Research,
National Health Research Institutes, Taipei, Taiwan
* cmliu1968@ntu.edu.tw
Annexin A7 (ANXA7) and protein phosphatase 3 (formerly
2B), catalytic subunit, beta isoform (PPP3CB) have been
reported associated with schizophrenia in our previous
association studies. The aim of the study is to search for the
risk polymorphisms of the two genes for schizophrenia using
systematic mutation screening method. We have sequenced
the exons and the promoter regions of the two genes in 50
controls and 42 schizophrenic patients. We have identified 16
and five genetic variations of ANXA7 and PPP3CB,
respectively. and 11 genetic variations of them have been
genotyped in a large case-control sample, including 600
supernormal controls and 912 schizophrenic patients. We
found the C allele of a novel SNP (PPP3CB-1) in the promoter
region, and the C allele of SNP rs58876184 in the 3’UTR
region of PPP3CB, is significantly over-represented in the
case groups (p = 0.038 and 0.018, respectively). The haplotype
composed of the four genetic variations of PPP3CB also
showed significant haplotype frequency difference between
the cases and controls. Our data showed the genetic variations
in the promoter region and 3’ UTR region of PPP3CB is
probably related to genetic vulnerability of schizophrenia.
Further clarification of the biological function of the two
genetic variations is ongoing.

236 ASSOCIATION BETWEEN NRG-1 MARKERS AND
REGIONAL BRAIN MORPHOMETRY IN PSYCHOTIC
DISORDERS
A. Dutt* (1,2), C. McDonald (1,2), E. Dempster (1,2), D.
Prata (1,2), M. Shaikh (1,2), I. Williams (1,2), S. Amankwa
(1,2), K. Schulze (1,2), N. Marshall (1,2), M. Walshe (1,2), M.
Allin (1,2), D. Collier (1,2), R. Murray (1,2), E. Bramon (1,2)
1. NIHR Biomedical Research Centre, Institute of Psychiatry
(King’s College London)/South London 2. Maudsley NHS
Foundation Trust, London, UK
*Anirban.Dutt@kcl.ac.uk
Introduction: Lateral ventricular enlargement and hippocampal
volume deficits are commonly observed morphometric
abnormalities in psychotic disorders such as schizophrenia and
psychotic bipolar disorder. The neuregulin gene (NRG1) has
been associated with both these disorders, and it is believed to
regulate different neurodevelopmental processes including
neuronal and glial cell survival, proliferation, migration and
differentiation. In our study we investigated the effect of
NRG-1 markers on lateral ventricular and hippocampal
volumes in psychosis. Methods: 360 participants comprising
of patients with psychosis, their family members, and
unrelated healthy controls of white European ancestry
underwent structural MRI and genotyping. The
NRG-1 markers consisted of one single nucleotide
polymorphism marker (SNP8NGR22153) and two
micro-satellites (478B14-848 and 420 M9-1395). The effect of
candidate genes on brain morphometry was examined using
linear regression models adjusting for clinical group, age, sex
and correlations between members of the same family.
Results: There was no evidence of association between the
NRG-1 markers and either ventricular or hippocampal
volumes. Conclusion: Our study demonstrates that the
neuregulin gene does not influence ventricular or hippocampal
volumetric deficits in psychotic disorders. Although the
neuregulin gene has been associated with both schizophrenia
and bipolar disorder, it must have very modest influence on
regional morphometric deviations on its own.
237 IDENTIFYING CNV’S IN SCHIZOPHRENIA
USING MULTIPLEX AMPLICON QUANTIFICATION
(MAQ) AND THEIR VERIFICATION BY FISH
M. Malloy* (1), J. Del-Favero (2), D. Goossens (2), L.
Heyrman (2), A. Laenerts (2), D. St Clair (3), D. Blackwood
(4), W. Muir (4), B. Pickard (5)
1. Molecular Medicine Centre, University of Edinburgh
2. University of Antwerp 3. University of Aberdeen
4. University of Edinburgh 5. University of Strathclyde
*Pat.Malloy@ed.ac.uk
Schizophrenia is a chronic and disabling mental illness that
affects around 1% of the world’s population. Although a
genetic basis for the disorder is not disputed, our
understanding of the risk factors involved until recently has
been very limited. We have shown that chromosomal
abnormalities such as reciprocal balanced translocations, can
act as direct positional pointers by disruption, to schizophrenia
risk genes. DISC1, PDE4b (Miller K., Pickard B. et al.
Science 310 (5751): 1187-1191, 2005) and NDEL1
(unpublished) are either directly disrupted, or immediately
proximate to chromosomal breakpoints. Our hypothesis is that
such breakpoints lie near LCRs which should also predispose
to microdeletions and microduplications that comprise CNV.
We are using Multiplex Amplicon Quantification (MAQ,
Sutrala et al Scz Res 96 (1-3): 93-9), firstly to detect CNVs
found by Walsh et al (Science 320 (5875): 539-43, 2008) and
Kirov et al (Hum Mol Gen 17 (3): 458-65) in large
case-control cohorts of schizophrenia (n=1000), co-morbid
Learning Disability and Schizophrenia (n=200), bipolar
disorder (n=400) and major depressive disorder (n=400).
Secondly we have analysed regions around DISC1 pathway
genes in a site directed approach to quantify the allelic
variation in the same patients. Sex-matched controls (normal
and learning disabled alone) are available for comparator
purposes. FISH is used at the BAC or Fosmid level on
metaphase or interphase preparations, or where applicable
additional information from our GWAS data, to confirm any
variation

238 THE REGULATION OF SUSCEPTIBILITY GENES
FOR SCHIZOPHRENIA
F. Macciardi* (1), E. Osimo (2), S. Potkin (1), F. Torri (2), J.
Fallon (1), J. Turner (1), G. Guffanti (1), M. Vawter (1), B.
Lerer (3), S. Gaudi (4)
1. UCI 2. UNIMI 3. Hadassah 4. ISS (Roma)
*fmacciar@uci.edu
The complexity of the genome has little to do with the number
and heterogeneity of its genes: only 2% of the human genome
codes for proteins, while 45% consists of Transposable
Elements (TEs). The relative amount of TEs increases
consistently with organism complexity, the TEs domains of
the regulatory genome drive genome evolution, alter gene
expression and can substantially contribute to the etiology and
characteristics of complex diseases. The regulation of TE
expression has been already associated with complex diseases
and cancer cells are characterized by high expression levels of
LINE-1, correlating cancer cell to the reactivation of retroviral
transcripts (RT) expression. Moreover, complex human
diseases cannot be explained by genetic factors alone and are
likely to be the result of gene-environment interactions with
the contribution of TEs. The detection of retroviral transcripts
in the brains of schizophrenics suggests that activation or
upregulation of distinct human endogenous retroviruses
(HERVs) may play a role in the etiopathogenesis of
neuropsychiatric diseases. Our aim is to propose a novel
mechanism for gene dysregulation in schizophrenia by
investigating the functional relationship between TE and genes
identified as "best" candidate from GWAS, validating them
with exon-expression arrays and reconstructing their
regulatory network with computational methods. We found
preliminary evidence of alternative regulation of
tissue-specific gene expression in schizophrenic patients from
genes that we identified as associated with schizophrenia from
our GWAS. We present results for both tissue specific
expression and alternative Transcription Starting Sites (TSS)
in pivotal disease-related genes.
239 GENE EXPRESSION PROFILES OF CULTURED
NEURAL PROGENITOR CELLS DEMONSTRATE
DIFFERENTIAL EXPRESSION OF
DEVELOPMENTAL-RELATED GENES IN
SCHIZOPHRENIA
O. Evgrafov* (1), B. Wrobel (1), X. Kang (1), G. Simpson
(1), D. Malaspina (2), J. Knowles (1)
1. USC 2. NYU
*evgrafov@keck.usc.edu
We investigated the expression of poly-A RNA isolated from
cultured neuronal cells derived from olfactory
neuroepithelium (CNON) of 8 patients with schizophrenia
(SZ) and 8 control individuals. Human neuroepithelium
constantly produces olfactory neurons from neural stem cells
and this process is simulated in CNON cultures, which are
primarily composed of neuronal progenitors. The tight
environmental control provided by cell culture provided a high
signal-to-noise ratio and yielded a clear separation of SZ and
control samples, in a principle component analysis. In
contrast to neurons from adult brain, CNON cells express
genes that are specific for development of neural system. We
measured gene expression using Human Exon 1.0 ST Arrays
(Affymetrix) followed by ANOVA analysis using Partek GS
(Partek). We have also performed RNA-Seq using an
Illumina Genome Analyzer II, on a portion of these samples.
The top most differentially expressed genes were validated by
qPCR. The three most differentially expressed genes were
CDH6, VCAM1 and S1PR1 (EDG1). Another cadherin,
CDH11, was also differentially expressed, when validated by
qPCR. Three of these are cell adhesion molecules, and the
fourth, S1PR1, directly regulates cadherin expression and is
involved in regulation of VCAM1. Cell adhesion molecules
are known to play an important role in brain development and
the observation of lower levels of these molecules in the SZ
group may point to a possible mechanism for the altered
neurodevelopment observed in individuals with schizophrenia.

240 SIGNIFICANT LINKAGE AT CHROMOSOME
2p15 TO A SCHIZOPHRENIA ENDOPHENOTYPE IN A
NEPALESE POPULATION GENETIC ISOLATE
S. Santangelo* (1), T. Sitnikova (1), M. Hall (2), P. Shrestha
(3), D. Yu (4), J. Subedi (5), S. Ojha (6), S. Tamang (3), R.
Chapagain (3), S. Kamar (3), J. VandeBerg (7), J. Blangero
(7), S. Williams-Blangero (7)
1. Harvard Medical School, Dept Psychiatry, Center for
Human Genetic Research, Massachusetts General Hospital,
Boston, MA, USA 2. Psychology Research Laboratory,
McLean Hospital, Belmont, MA, USA 3. Nepal Biomedical
Research Center, Kathmandu, Nepal 4. Center for Human
Genetic Research, Massachusetts General Hospital, Boston,
MA, USA 5. Miami University, Dept. Sociology,
Gerontology, Oxford, OH, USA 6. Tribhuvan University
Institute of Medicine, Dept. Psychiatry, Kathmandu, Nepal
7. Southwest Foundation for Biomedical Research, San
Antonio, TX, USA
*ssantangelo@pngu.mgh.harvard.edu
Electrophysiological traits indexing schizophrenia
endophenotypes were measured in over 600 members of an
extended pedigree in Jiri, Nepal. In an auditory "oddball"
paradigm, we recorded peak amplitude and latency of the
P300 evoked response as well as power of oscillatory brain
activity in the gamma-band range (35-45Hz) induced between
250-550 msec after odd tones onset. To examine
anterior-posterior and hemispheric differences, the data were
examined at Fz, Pz, P3 and P4 scalp locations and evaluated in
a quantitative trait locus genome-wide linkage analysis.
Heritabilities for both P300 amplitude and induced gamma at
Pz, P3, and P4, and for P300 latency at P4 were significant.
For this Nepalese pedigree and marker set, evidence of
suggestive linkage is obtained for LOD scores ≥ 1.65, and
significant linkage for LODs ≥ 2.83. Peak LODs for the ERPs
were 2.93 at chromosome 2 (87 cM) for Pz amplitude, 2.07 at
chromosome 13 (76 cM) for Fz latency, and 2.32 at
chromosome 17 (61 cM) for P4 latency. QTL linkage results
for gamma response centered on chromosome 2p13 (98 cM)
with peak LOD scores of 1.31 for Pz, 1.42 for P3, and 1.84 for
P4. Thus, we obtained significant linkage for P300 amplitude
at 2p15 and suggestive linkage for induced gamma-band
response in the P300 time-window at 2p13; these loci are only
10 MB apart. Genes in this region include sepiapterin
reductase, an enzyme that catalyzes the final step in the
synthesis of tetrahydrobiopterin (BH4), an essential cofactor
for synthesis of many neurotransmitters, including serotonin.
242 COMT GENOTYPE, COGNITION, AND
FUNCTIONAL CAPACITY IN SCHIZOPHRENIA
E. Twamley* (1), C. Burton (1), V. Lea (1), G. Savla (1), J.
Guidry (1), M. Abeles (1), A. Minassian (1), R. Bilder (2), J.
Kelsoe (1)
1. University of California, San Diego 2. University of
California, Los Angeles
*etwamley@ucsd.edu
The Val158Met single nucleotide polymorphism of the
catechol-O-methyltransferase (COMT) gene on chromosome
22 influences dopamine catabolism and is related to cognitive
impairment in schizophrenia. Previous research has found that
the Met allele is associated in a dose-response fashion with
better performance on most neuropsychological tests. We
assessed 116 outpatients with schizophrenia-spectrum
disorders (62% men; 68% Caucasian; mean age=48; mean
years of education=13) with a blood draw and a
comprehensive neuropsychological, functional, and clinical
battery. Participants with the Val/Val (n=38), Val/Met (n=53),
and Met/Met (n=25) genotypes did not differ on demographic
variables, diagnosis, type or dosage of antipsychotic
medication, or duration of psychosis. Spearman correlations
between the “dose” of the Met allele (0, 1, or 2 Met alleles)
and the neuropsychological, functional, and clinical variables
demonstrated that a higher number of Met alleles was
associated with better estimated premorbid intellectual
functioning (r=.21, p=.028). Correlations between the number
of Met alleles and performance on the UCSD Performance
Based Skills Assessment (Household Chores and Recreation
Planning subtests) were >.15, but did not reach statistical
significance. Met homozygotes significantly outperformed Val
homozygotes on the UPSA Household Chores subtest (t=2.0,
df=59, p=.049). The Met allele appears to be associated with
better performance in selected neuropsychological domains
and functional capacity tasks. Because the Val158Met
polymorphism typically explains a small amount of variance
in cognitive performance and given the size of the current
sample, these results need to be replicated with a larger sample
and other variants should be considered to further understand
genetic contributions to cognition.

243 CONSANGUINITY AND INCREASED RISK FOR
SCHIZOPHRENIA IN EGYPT
H. Mansour* (1, 2), W. Fathi (2), L. Klei (1), J. Wood (1), K.
Chowdari (1), A. Watson (1), A. Eissa (2), A. Yassin (2), H.
Salah (2), S. Tobar (2), H. El-Boraie (2), H. Gaafar (2), M.
Elassy (2), I. Ibrahim (2), N. Ibrahim (1), K. Kandil (1), W.
El-Bahaei (2), M. Alatrouny (2), F. El-Chennawi (3), B.
Devlin (4), V. Nimgaonkar (1, 5)
1. Department of Psychiatry, University of Pittsburgh School
of Medicine, Western Psychiatric Institute and Clinic,
Pittsburgh, Pennsylvania 2. Department of Psychiatry,
Mansoura University School of Medicine, Mansoura, Egypt
3. Department of Clinical Pathology, Mansoura University
School of Medicine, Mansoura, Egypt 4. Department of
Human Genetics, Graduate School of Public Health,
University of Pittsburgh, Pittsburgh, Pennsylvania
5. Department of Human Genetics, Graduate School of Public
Health, University of Pittsburgh, Pittsburgh, Pennsylvania
*mansourha@upmc.edu
Background: Consanguinity has been suggested as a risk
factor for psychsoses in some Middle Eastern countries, but
adequate control data are unavailable. Our recent studies in
Egypt have shown elevated parental consanguinity rates
among patients with bipolar I disorder (BP1), compared with
controls. We have now extended our anlayses to
Schizophrenia (SZ) in the same population. Methods: A
case-control study was conducted at Mansoura University
Hospital, Mansoura, Egypt (SZ, n = 75; controls, n = 126, and
their available parents). The prevalence of consanguinity was
estimated from family history data (‘self report’), followed by
DNA analysis using short tandem repeat polymorphisms
(STRPs, n = 64) (‘DNA-based’ rates). Results: Self reported
consanguinity was significantly elevated among the patients
(SZ: 45%, controls: 18%, OR 3.7, 95% CI 1.95, 7.05; p =
0.0001, 1 d.f.). These differences were confirmed using DNA
based estimates for coefficients of inbreeding (inbreeding
coefficients, mean ± standard error, cases: 0.058 ± 0.007,
controls: 0.022 ± 0.003, test statistic = -6.76, p = 6.6 e-12).
Conclusion: Consanguinity rates are significantly elevated
among Egyptian SZ patients in the Nile delta region. The
associations are similar to those observed with BP1 in our
earlier study. If replicated, the substantial risk associated with
consanguinity raises public health concerns.
244 ADMIXTURE ANALYSIS OF AGE AT ONSET IN
SCHIZOPHRENIA: GENETIC ASSOCIATION STUDY
OF 384 MARKERS ACROSS THE GENOME
V. De Luca* (1), F. Panariello (1), C. Zai (1)
1. University of Toronto
*vincenzo_deluca@camh.net
Despite the considerable amount of data from several studies,
none of the thresholds used to define age at onset (AAO) in
schizophrenia have been validated. The aim of this study is to
assess the presence of different homogenous subgroups in
schizophrenia patients based on the age at onset, by
determining the cut-off age of each subgroup. Admixture
analysis was applied to identify model(s) of separate normal
distributions of AAO characterized by different means,
variances and population proportions. This helped us in
identifying different subgroups in our sample of 466 patients
with schizophrenia. We apply now a candidate gene
association strategy aimed to detect genetic susceptibility for
early onset in patients’ schizophrenia by using a custom
Illumina Bread Chips comprising 384 SNPs selected among
candidate genes implicated in the neurobiology of
schizophrenia. We analyzed 154 schizophrenic patients from
White European ancestry recruited in Toronto at the Centre for
Addiction and Mental Health. Thirty-four patients who had a
psychotic onset when they were younger than 20 (optimal
cut-off from admixture analysis) were considered early onset
schizophrenics. By using a GWA-like approach, we screened
all 384 markers for the nominal significance level and then
corrected for multiple test. The most significant SNP was the
rs460401 (p=0.0003) however after the False Discovery Rate
correction the p-value was not significant (p=0.113). Our
analysis of 384 markets across candidate genes revealed that
the SNP rs460401 located in the Ionotropic Kainate 1
Glutamate receptor (GRIK1) is associated with early onset in
schizophrenia. This preliminary result pointed out the
importance of the kainate receptors in determining the onset of
schizophrenia therefore further work on these genes regarding
this phenotype is required.

245 GENOME-WIDE ASSOCIATION STUDY OF
MULTIPLEX SCHIZOPHRENIA PEDIGREES
SUPPORTS A ROLE FOR CONTACTIN PROTEINS
D. Levinson* (1), J. Shi (1), B. Riley (2), A. Pulver (3), M.
Owen (4), D. Wildenauer (5), P. Gejman (6), B. Mowry (7), C.
Laurent (8), S. Oh (1), K. Kendler (2), G. Nestadt (3), N.
Williams (4), S. Schwab (5), A. Sanders (6), D. Nertney (7), J.
Mallet (9), B. Wormley (2), V. Lasseter (3), M. O'Donovan
(4), J. Duan (6), M. Albus (10), M. Alexander (1), D. Cohen
(8), R. Ribble (2), K. Liang (11), N. Norton (4), W. Maier
(12), G. Papadimitriou (13), D. Walsh (14), M. Jay (8), A.
O'Neill (15), F. Lerer (16), D. Dikeos (13), M. Fallin (3), J.
Silverman (17), M. Hansen (18), F. Dudbridge (19), P.
Holmans (4)
1. Stanford University, Stanford, CA 2. Virginia
Commonwealth University, Richmond VA, USA 3. Johns
Hopkins University, Baltimore, MD, USA 4. Cardiff
University, Cardiff, UK 5. University of Western Australia,
Perth 6. NorthShore University Healthcare Research Inst,
Evanston,IL 7. University of Queensland, Brisbane, Australia
8. Pierre et Marie Curie Faculty of Medicine, Paris 9. CNRS,
Hôpital de la Pitié Salpêtrière, Paris 10. State Mental Hospital,
Haar, Germany 11. Johns Hopkins University Bloomberg
School of Public Health, Baltimore MD 12. University of
Bonn, Bonn, Germany 13. University of Athens Medical
School, Athens, Greece 14. The Health Research Board,
Dublin, Ireland 15. Queens University, Belfast, Northern
Ireland 16. Hadassah-Hebrew University Medical Center,
Jerusalem, Israel 17. Mt. Sinai School of Medicine, New
York, NY, USA. 18. Illumina, Inc. La Jolla, CA 19.
Biostatistics Unit, Cambridge, UK
*dflev@stanford.edu
We carried out a genome-wide association study (GWAS) of
DSM-IIIR schizophrenia and schizoaffective disorder in
multiply-affected families. Families ascertained by seven
previous linkage studies (and not included previously in
GWAS) were selected if they had constellations of genotyped
individuals informative for family-based association analysis
(≥1 affected cases with 1-2 parents and/or unaffected siblings;
or ≥3 affected cases). Genotyping was carried with the
Illumina 610-quad array. QC analyses excluded
poorly-performing DNA samples and SNPs, confirmed family
relationships and sex, and established ancestries. Following
QC, there were 583 European-ancestry families with 2212
genotyped individuals (1218 affected), and 50 families with
other ancestries (primarily large pedigrees with known
admixture, analyzed in separate subsets) with 253 genotyped
individuals (139 affected). Single-SNP association analyses
were carried out with TRANSMIT (autosomal SNPs) and
UNPHASED (X chromosome SNPs), after preliminary testing
to ensure comparability of the methods and correct Type I
error rates. No genome-wide significant results (P < 5 x 10-8)
were observed in analyses of European-ancestry or all
families. Among genes containing one or more SNPs with
P-values < 10-4, five encode cell adhesion molecules
(CNTNAP5, AMIGO3, CADM2, CLEC4D, CLEC4E), and
P-values < 10-3 were observed for clusters of SNPs in
CNTNAP2 and CNTN5. Genes in the related CNTNAP and
CNTN families (and the larger neurexin family) have been
proposed as implicated in both autism and schizophrenia
based on several lines of evidence, including cases with
structural variants (for review see Burbach and van der
Zwaag, Trends Neurosci, 2009;32:69-72). Larger samples and
additional lines of evidence will be required to determine the
significance of these findings.
246 RUNS OF HOMOZYGOSITY NOT ASSOCIATED
WITH INCREASED RISK OF SCHIZOPHRENIA
M. Simonson* (1), M. McQueen (1), M. Keller (1)
1. Institue for Behavioral Genetics; University of Colorado at
Boulder
*masimonson@gmail.com
Previous research suggests that runs of homozygosity are a
risk factor for schizophrenia (Lencz et al, 2007). We used
700000 SNP markers on 2357 schizophreniacases and 2709
controls to find runs of homozygosity. We assessed rare
versus common runs as well as runs that did or did not overlap
genes. Analyses showed no case-control differences in the
percent of the genome in runs of homozygosity. Our analyses
suggest that runs of homozygosity are not associated with
increased risk of schizophrenia.
247 FUNCTIONAL ANALYSIS OF GENETIC
VARIATION AT THE DTNBP1 LOCUS.
L. Carroll (1), A. Gerrish (1), L. Elliston (1), G. Kirov (1), M.
Owen (1), M. O'Donovan (1), N. Williams* (1)
1. Cardiff University
*williamsnm@cf.ac.uk
A large volume of genetic association data from multiple
populations now supports the locus encoding Dysbindin
(DTNBP1) as a schizophrenia susceptibility gene. The source
of the genetic association at Dysbindin is equivocal, however
studies to date show altered protein and mRNA levels in
schizophrenic CNS. Furthermore, there is evidence to suggest
that cis acting variation alters Dysbindin mRNA levels in
post-mortem neural tissue and is correlated with a replicated
schizophrenia “at-risk” haplotype. To identify the functional
variation causing the association at DTNBP1 we have
performed resequencing and high-density association mapping
in large case-control and familial schizophrenia samples from
Europe. Associated variants have been analysed to see
whether they account for the changes in mRNA levels
observed in post-mortem brain by performing allele specific
expression studies in extended samples of those previously
reported.

248 MITOCHONDRIAL DNA AND SCHIZOPHRENIA
B. Verge (1), Y. Alonso (1), C. Miralles (1), J. Valero (1), S.
Setó (1), A. Labad (1), E. Vilella (1), L. Martorell (1)
1. HPUIPM, IISPV, URV
One of the hypotheses about the genetic factors involved in
schizophrenia points out the mitochondrial DNA (mtDNA), a
16569 bp molecule which is inherited only from the mother
(about 100.000 copies) and involved in maternally inherited
mitochondrial disorders. If this hypothesis is true, one would
expect a higher frequency of schizophrenia in relatives that
share the mtDNA with a schizophrenic patient than in relatives
that do not share. We have interviewed 100 schizophrenia
patients according to DSM-IV criteria and 147 relatives to
collect clinical data from both sides of the patient’s pedigree.
Thirty one schizophrenia patients present at least one first-
and/or one second-degree relative affected by schizophrenia,
meanwhile the remaining 69 were sporadic cases. Apparent
matrilineal inheritance was present in 22 of the 31 familial
cases (71%). According to the 31 familial cases, information
about mental health was achieved from 588 relatives through
direct interview to one or two first degree relatives. Four
groups were established to compare the presence of
schizophrenia in relatives depending on they share or not the
mtDNA with a schizophrenia patient. Relatives that share the
mtDNA with a schizophrenic patient have a higher risk of
developing the illness than those that do not share, OR=4.82
(CI 2.04-13.11, p=0.00005). Evidence is accumulating that
mitochondrial dysfunction is involved in the pathophysiology
of schizophrenia and large studies are necessary to corroborate
the involvement of mtDNA in the development of the illness.
249 INITIAL LINKAGE ANALYSES OF SIX
ENDOPHENOTYPES FOR SCHIZOPHRENIA FROM
THE CONSORTIUM ON THE GENETICS OF
SCHIZOPHRENIA (COGS)
T. Greenwood* (1), K. Cadenhead (1), M. Calkins (2), D.
Dobie (3), R. Freedman (4), M. Green (5), R. Gur (2), L.
Lazzeroni (6), G. Light (1), K. Nuechterlein (5), A. Olincy (4),
A. Radant (3), L. Seidman (7), L. Siever (8), J. Silverman (8),
W. Stone (7), N. Swerdlow (1), D. Tsuang (3), M. Tsuang (1),
B. Turetsky (2), N. Schork (9), D. Braff (1)
1. Department of Psychiatry, University of California San
Diego, La Jolla, CA 2. Department of Psychiatry, University
of Pennsylvania, Philadelphia, PA
3. Department of Psychiatry and Behavioral Sciences,
University of Washington, and the VA Puget Sound Health
Care System, Seattle, WA 4. Department of Psychiatry,
University of Colorado Health Sciences Center, Denver, CO
5. Department of Psychiatry and Biobehavioral Sciences,
Geffen School of Medicine at University of California Los
Angeles, Los Angeles, CA 6. Department of Psychiatry and
Behavioral Science, Stanford University, Stanford, CA
7. Department of Psychiatry, Harvard Medical School,
Massachusetts Mental Health Center Public Psychiatry
Division of the Beth Israel Deaconess Medical Center and the
Harvard Institute of Psychiatric Epidemiology and Genetics,
Boston, MA 8. Department of Psychiatry, The Mount Sinai
School of Medicine, and the James J. Peters VA Medical
Center, New York, NY 9. Scripps Genomic Medicine, La
Jolla, CA
*tgreenwood@ucsd.edu
As part of the COGS, we have recently completed genotyping
and preliminary analyses of a genome-wide SNP linkage scan
for 211 families of schizophrenia probands comprising the
first phase of our data release. Genotyping was performed
using the Illumina Linkage Panel 12 containing 6,090 SNP
markers across the genome. We used Merlin to conduct
linkage analyses of the 6,001 SNPs that were successfully
assayed, accounting for linkage disequilibrium between
markers and accommodating the appropriate covariates (age
and sex) for each endophenotype. We have currently
completed these analyses for each of our six primary
neurophysiologicaland neurocognitive endophenotypes:
Prepulse inhibition (PPI), P50 suppression, the antisaccade
task, the Continuous Performance Test
(Degraded-Stimulusversion, DS-CPT), the Letter-Number
Span (LNS), and the California VerbalLearning Task (CVLT).
Analyses of endophenotypes from the Pennsylvania
Computerized Neuropsychological Battery and several
secondary endophenotypes are currently in progress. Thus far
these analyses have collectively identified regions of linkage
with LOD scores>3.0 on chromosomes 5p (PPI) and 10q
(DS-CPT), of which the chromosome 10qlinkage meets
genome-wide criteria for ‘significant’ linkage. We also
observed ‘suggestive’ evidence for linkage (LOD>2.2) on
chromosomes 1q (antisaccade), 3p (DS-CPT), and 14q(LNS).

These findings are encouraging and suggest that we will
ultimately be successful in identifying genes contributing to
the expression of these endophenotypes. However, we note
that these analyses are preliminary, as this sample will be
supplemented with our remaining 94 families currently being
prepared for submission for genotyping, after which the final
linkage analyses will be performed.
250 SEARCHING THE CORRELATED MARKERS OF
NRG1 IN POSTMORTEM BRAIN.
M. Lee* (1), S. Yim (1)
1. Seoul National Hospital
*migyunglee37@gmail.com
Neuregulin1- ErbB4 signal has a critical role in understanding
of the schizophrenia pathophysiology. NRG1 expression
abnormalities have been observed in patients and mice. So, we
search the NRG1 expression by using the Stanley
Neuropathology Consortium Integrative Database (SNCID)
which is a web-based method to integrate the Stanley Medical
research Institute data sets. We found that cytoplasmic protein
level of 53KD NRG1 intracelluar cleavage domain (ICD) is
significantly increased in cytoplasmic fractions of
schizophrenia (n=15) compared with normal control(n=15,
p≤0.001), depression(n=15, p≤0.01) and bipolar affective
disorder(n=15, p≤0.01). Spearman’s test exhibited that 53 KD
NRG1 level is significant correlated with glutamic acid
decarboxylase( GAD)(p=0.007) at orbitofrontal cortex/III,
NMDA receptor subunit zeta(p=0.009) at frontal lobe and total
cathechol –o-methyltransferase (COMT) (p=0.007) at
Brodmann area 46. It is well known about relation between
NRG1 and glutamate system in schizophrenia, but not in
NRG1 and COMT. COMT is a risk factor for psychosis and
metastatic cancer. Sei et al reported the evidence of epistatic
interaction between COMT gene and NRG1 gene at
schizophrenia derived B lymphocytes. Although it was not
elucidated about COMT gene and NRG1 gene interaction in
these results, it addressed the novel possibility of epistatic
interaction evidence in postmortem brain.
251 QKI-7 REGULATES EXPRESSION OF
INTERFERON-RELATED GENES IN HUMAN
ASTROCYTES
L. Jiang (1), E. Lindholm Carlstrom* (1), P. Saetre (2), E.
Jazin (1)
1. Uppsala University 2. Karolinska Institute
*eva.lindholm@ebc.uu.se
The gene the quaking homolog, KH domain RNA binding
(mouse) (QKI), is a candidate gene for schizophrenia encoding
an RNA-binding protein and was recently shown to be
essential for myelination in oligodendrocytes. QKI is also
expressed in astrocytes, but its function in these cells is not
known. We studied the effect of small interference RNA
(siRNA)-mediated QKI depletion on global gene expression in
human astrocyte glioma cells. The most significant alteration
after QKI silencing was the decreased expression of genes
involved in interferon (IFN) induction (P = 6.3×10-10). These
genes were down-regulated after silencing of the splice variant
QKI-7, but were not affected by QKI-5 silencing.
Interestingly, four of them were up-regulated after treatment
with the antipsychotic haloperidol that also resulted in
increased QKI-7 mRNA levels. Our results suggest a novel
role for QKI-7 as a regulator of IFN production in astrocytes.

252 ALLELIC VARIATION IN THE MICRORNA
GENE, HSA-MIR-943, AFFECTS THE RISK OF
SCHIZOPHRENIA
M. Barenboim* (1), R. Straub (1), R. Vakkalanka (1), D.
Weinberger (1)
1. Clinical Brain Disorders Branch, Genes, Cognition, and
Psychosis Program, National Institute of Mental Health, NIH
*barenboimm@mail.nih.gov
MicroRNAs (miRNAs) are short (~22 nt) regulatory,
non-coding RNAs. Primary miRNA transcripts form
characteristic stem-loop structures. In the nucleus, pri-miRNA
is first processed into pre-miRNA (~100 nt) by Drosha and
after exported in the cytoplasm, into mature miRNA by Dicer.
miRNA integrated into the RISC complex, binds to the
3’UTR of a target mRNA and represses gene expression on
the post-transcriptional level. Disease-associated SNPs are
known to modulate gene expression. Hence, the study of SNPs
located either in a miRNA gene or in the miRNA target site is
of importance. We have identified 12 HapMap CEU SNPs
located in miRNA genes. 7 SNPs were tested with the
software suite, Unphased, for association with schizophrenia
using family-based data from the GCAP/NIMH Sibling Study.
One of these SNPs (rs1077020), which was located in the
stem-loop structure of hsa-miR-943, was nominally associated
with schizophrenia (p = 0.03). A subsequent
semi-independent case-control test of rs1077020 corroborated
the association of this SNP with schizophrenia (p = 0.0005).
hsa-miR-943 is located in the junction of an intron and ORF of
the WHSC2 gene and also in the 5’UTR of one isoform. The
test for association with schizophrenia of 13 HapMap SNPs in
WHSC2 was negative. RNA secondary structure analysis
shows that allele ‘G’ reduced the stability of the stem-loop
structure. This could lead to a reduction in the yield of mature
hsa-miR-943 and weaken the regulation and control of the
target gene. The predicted list of genes targeted by
hsa-miR-943 includes prominent candidate schizophrenia
genes such as DISC1, BDNF, STX18, SLC1A3.
253 THE SCHIZOPHRENIA SUSCEPTIBILITY GENE
ZNF804A CONTAINS POLYMORPHISM
INFLUENCING ITS EXPRESSION IN BRAIN
M. Hill* (1), F. Buonocore (1), N. Bray (1)
1. Centre for the Cellular Basis of Behaviour, Department of
Neuroscience, The James Black Centre, Institute of
Psychiatry, Kings College London, 125 Coldharbour Lane,
London, SE5 9NU, UK
*matthew.hill@kcl.ac.uk
Genome-wide association studies have identified ZNF804A as
a susceptibility locus for schizophrenia. Although ZNF804A is
known to contain several non-synonymous variants, these do
not appear to fully account for the observed association signal.
Indeed, the most strongly associated polymorphism is located
in a non-coding region of the gene, suggesting that the
susceptibility is mediated, at least in part, by effects on
ZNF804A expression. We screened 10 human brain regions
for the presence of cis-acting effects on ZNF804A expression
using highly quantitative measures of relative allelic
expression. We found statistically significant departures from
the expected 1:1 allelic ratio of ZNF804A expression in
several individuals, indicating the presence of cis-regulatory
polymorphism. Furthermore, within individuals, these
cis-regulatory effects were limited to specific brain regions.
Investigation of the relationship between
schizophrenia-associated variants and observed distortions in
allelic expression will enable assessment of the role of
ZNF804A expression in schizophrenia susceptibility and the
brain regions that are likely to be primarily involved.

254 EVALUATION OF GENETIC ASSOCIATION
BETWEEN SCHIZOPHRENIA AND RHEUMATOID
ARTHRITIS
J. Park* (1), H. Lee (2), H. Kim (3), S. Kang (3), S. Kim (3),
A. Cho (1), J. Kim (4), J. Chung (3)
1. Department of Psychiatry, Kyung Hee University East-West
Neo Medical Center, Seoul, Korea 2. Department of
Pharmacology, College of Medicine, Kangwon National
University, Chuncheon, Korea 3. Kohwang Medical Research
Institute, School of Medicine, Kyung Hee University, Seoul,
Korea 4. Department of Neuropsychiatry, School of Medicine,
Kyung Hee University, Seoul, Korea
*parkdawit@naver.com
Introduction: Schizophrenia and rheumatoid arthritis (RA) are
both chronic diseases with a strong genetic component. The
association between schizophrenia and RA was confirmed in
many studies, providing clues as to the common genetic
etiology. To find common genetic factors between two
diseases, a genome-wide association study was performed.
Methods: 100,000 single nucleotide polymorphisms (SNPs)
were evaluated by Illumina Infinium® DNA Analysis
BeadChips in 24 patients with schizophrenia, 24 patients with
RA, and 34 controls of Korean population.
Results: Two SNPs (one from EPM2AIP1 gene on
chromosome 3; the other from KLHL1 gene on chromosome
13) were found to be associated with SPR and RA
simultaneously. There were no significant differences in the
genotype and allele frequencies of the two SNPs between the
two diseases. Discussion: These results suggest the possibility
that schizophrenia and RA have a common etiologic factor in
the genetic level, and the genetic factor may explain the
association between the two diseases.
291 MICRODUPLICATIONS OF 16P11.2 ARE
ASSOCIATED WITH SCHIZOPHRENIA
S. McCarthy (1), G. Kirov (2), A. Addington (3), J.
McClellan (4), M. Kusenda (1), O. Krastoshevsky (5), R.
Kumar (6), T. Crow (7), S. Christian (6), J. Lieberman (8), F.
McMahon (3), A. Malhotra (9), J. Potash (10), T. Schulze (3),
E. Leibenluft (3), J. Sutcliffe (11), D. Skuse (12), M. Gill (13),
N. Mendell (14), N. Craddock (2), M. Owen (2), M.
O’Donovan (2), T. Shaikh (15), E. Susser (16), L. DeLisi (17),
P. Sullivan (18), C. Deutsch (19), J. Rapoport (3), D. Levy (5),
M. King (4)
1. Cold Spring Harbor Laboratory 2. Cardiff University 3.
National Institute for Mental Health 4. University of
Washington 5. McLean Hospital 6. University of Chicago 7.
The Prince of Wales International Center for SANE Research
8. Columbia University 9. The Zucker Hillside Hospital 10.
Johns Hopkins School of Medicine 11. Vanderbilt University
12. University College London 13. Trinity College Dublin 14.
State University of New York 15. The Children's Hospital of
Philadelphia 16. Columbia University 17. Harvard Medical
School 18. University of North Carolina 19. University of
Massachusetts Medical School
An increase in the burden of rare copy number variants
(rCNVs) and the association of recurrent rCNVs at 1q21,
15q11, 15q13 and 22q11 in schizophrenia implicate rCNVs in
the etiology of the disorder.We present the association of rare
16p11.2 microduplications with schizophrenia in a cohort of
1921 cases and 4062 controls (P=1.4x10-5, OR=25.4). This
association was replicated using an independent sample of
2645 cases and 2420 controls (P=0.022, OR=8.3) from GAIN
(phs000021.v2.p1). In a meta-analysis of psychiatric disorders,
the 16p11.2 microduplication was consistently observed at a
significantly greater frequency in schizophrenia and autism
than in corresponding controls, 0.3% vs. 0.03% (P=5x10-7)
and 0.46% vs. 0.02% (P=1.9x10-7) respectively. The
microduplication was observed at a higher frequency in
bipolar disorder (0.1% vs 0.03%, P=0.055). In contrast, the
reciprocal 16p11.2 microdeletion increased the risk of autism
specifically (0.78% vs. 0.02% OR=38.7, P=2.3x10-13).
Analysis of quantitative patient clinical data showed that
standardized head circumference based on the CDC growth
charts was significantly larger in microdeletion carriers and
moderately smaller in microduplication carriers (1.25 vs.
-0.28, P=0.0007). Our findings add 16p11.2 to the growing list
of hotspots that considerably increase the risk of
schizophrenia. The spectrum of diseases associated with
16p11.2 is consistent with phenotypic heterogeneity at other
schizophrenia risk loci and suggests that common
neurobiological pathways maybe shared between phenotypes
associated with 16p11.2 rearrangements. Finally the
association of 16p11.2 rearrangements with head
circumference point to a potential genetic basis for early brain
overgrowth in autism and observations of smaller brain
volume in schizophrenia.

STATISTICS AND BIOINFORMATICS
255 ESTIMATING THE ACCURACY AND
CONCORDANCE OF CURRENT METHODS FOR THE
DETECTION OF COPY NUMBER POLYMORPHISMS
IN WHOLE GENOME ASSOCIATION STUDIES
C. Vogler* (1), L. Gschwind (2), B. Röthlisberger (3), A.
Huber (3), J. Sigmund (2), D. de Quervain (6), A.
Papassotiropoulos (2)
1. Division of Molecular Psychology, University of Basel,
Basel, Switzerland. Life Science Training Facility, Biocentre,
University of Basel, Basel, Switzerland 2. Division of
Molecular Psychology, University of Basel, Basel,
Switzerland. 3. Center of Laboratory Medicine, Cantonal
Hospital, Aarau, Switzerland 4. Division of Psychiatry
Research, University of Zurich, Lenggstr. 31, 8029 Zurich,
Switzerland
*christian.vogler@unibas.ch
Background: Since the discovery that Copy Number
Polymorphisms (CNPs) - common Copy Number Variations -
may account for a large amount of genetic variation in
humans, great efforts have been put in the thorough and
reliable detection of CNPs. A special hybrid genotyping array
(Affymetrix SNP 6.0) has been designed to assess copy
number states throughout the genome using a total of 1.8
million genomic markers (~900,000 SNPs and ~900,000 Copy
Number Markers). Furthermore a software package (birdsuite)
applying the canary algorithm has been provided by the
BROAD Institute, which can be used to assign copy number
states across regions of common copy number polymorphisms
.Methods: In our study we individually genotyped 771 healthy
Swiss subjects using the Affymetrix SNP 6.0 Genechip. We
aimed at conducting a CNP analysis applying the canary
algorithm and to subsequently assess the accuracy of this
approach using Real-Time-quantitative PCR (RT qPCR) and
array Comparative Genomic Hybridzation (aCGH) as a
validation tool for CNPs. Results and Conclusion: Processing
of Affymetrix SNP 6.0 GeneChips worked well and the bird
suite software package could be successfully applied. CNP
analysis has been carried out using the Broad-CNP-Map
comprising 1316 CNPs. Applying the recommended quality
controls given by the BROAD institute, in a remaining sample
size of 724 individuals a total number of 11943 CNPs > 90kb
were detected. Evaluation of results with RT qPCR and aCGH
is currently under progress.
256 COMPARISON BETWEEN THREE DIFFERENT
APPROACHES FOR GENOME-WIDE
IDENTIFICATION AND ANALYSIS OF COPY
NUMBER VARIATIONS
L. Gschwind* (1), C. Vogler (1), I. Filges (2), J. Sigmund (1),
D. de Quervain (3), A. Papassotiropoulos (1)
1. Division of Molecular Psychology, University of Basel,
Basel, Switzerland Life Science Training Facility, Biocentre,
University of Basel, Basel, Switzerland
2. Division of Medical Genetics, Department of Biomedicine,
University Children’s Hospital, Basel, Switzerland
3. Division of Psychiatry Research, University of Zurich,
Zurich, Switzerland
*leo.gschwind@stud.unibas.ch
Background: Very recently Copy Number Variations (CNVs)
have been shown to affect different phenotypic traits such as
susceptibility to disease. Currently, methods for in silico
analysis to identify CNVs using hybrid genotyping array
intensity data are being developed. So far an extensive
evaluation of the robustness of these algorithms is still
lacking. Methods: We used Affymetrix SNP 6.0 GeneChip
data from 724 healthy Swiss individuals and investigated three
different CNV detecting algorithms (PennCNV, Birdseye and
CNAM). Subsequently to analysis, results of all three CNV
detection tools were compared to determine concordance. As
an independent quality control, we also used the Affymetrix
SNP 6.0 GeneChip to process DNA from three clinical
samples with verified large-scale structural variations. We
examined the viability of the three different algorithms to
detect the known genomic aberrations. Results and
Conclusion: Affymetrix SNP 6.0 GeneChips were processed
and algorithms could be successfully applied. Preliminary
results indicate that all three algorithms reliably detect sizable
structural variants. Analysis of concordance between the three
methods is currently under progress.

257 MACHINE-LEARNING APPROACHES FOR
GENOME-WIDE ASSOCIATION STUDIES OF MOOD
DISORDERS*FAYAZ SEIFUDDIN, MEHDI
PIROOZNIA, JENNIFER JUDY, PAMELA MAHON,
JAMES POTASH, PETER ZANDI
F. Seifuddin* (1), M. Pirooznia (1), J. Judy (1), P. Mahon (1),
J. Potash (1), P. Zandi (1)
1. The Johns Hopkins University School of Medicine, Mood
Disorders Program
*fseifud1@jhmi.edu
Mood disorders are highly heritable forms of major mental
illnesses. A major breakthrough in genetic association of
mood disorders was anticipated with the advent of genome
wide association studies (GWAS). However, to date few
major significant findings have been identified, which
suggests the complex genetic etiology of mood disorders,
requiring alternative approaches to analyzing GWAS data.
Machine learning (ML) and data mining methods have been
successfully employed for both supervised and unsupervised
learning to mine and identify biomarkers in gene expression
studies. In this study, we compared four ML methods, namely,
decision tree, Bayesian networks, support vector machine, and
neural networks, in the analysis of GWAS data on bipolar
disorder and major depression. Bipolar datasets were obtained
from the Genetic Association Information Network (GAIN)
and Welcome Trust Case Control Consortium (WTCCC)
bipolar samples. Major depression datasets were obtained
from GAIN depression and Genetics of Recurrent Early-onset
Depression (GENRED) samples. We chose one dataset for
each disorder as the training dataset and built SNP classifier
models to distinguish cases and controls. The classifiers were
then applied to the second test datasets and their accuracy for
classification was compared. Different feature selection
methods were explored in order to address the dimensionality
problem and improve the performance of the classifiers.
Results across the four methods will be presented for each
disorder. ML methods offer a novel approach to analyze
GWAS data, but their performance characteristics need to be
evaluated to better understand how they may be used to
unravel the complex genetic etiology of common mood
disorders.
258 BAYESIAN APPROACHES TO ANALYSING TRIO
DATA
E. Heron* (1), R. Anney (1), L. Gallagher (1), M. Gill (1)
1. Neuropsychiatric Genetics Research Group, Dept. of
Psychiatry, Trinity College Dublin, Ireland.
*eaheron@tcd.ie
For early onset psychiatric diseases such as ADHD and
Autism, trio data, consisting of two parents and an affected
child, can sometimes be collected for GWAS type analyses.
These statistical analyses aim to detect an association between
a disease locus (or a locus in LD with the disease locus) and
the particular disease phenotype under study. This trio data
differs from the usual case control type data used in the
majority of GWAS studies, as data from an explicit control
group is not collected. GWAS analyses for trio data are
usually carried out using the transmission disequilibrium test
(TDT). The TDT examines transmissions and
non-transmissions of alleles from heterozygous parents to
probands, thus creating pseudo-controls for comparisons. A
Bayesian approach to examine associations for trio data is
presented. This approach uses Bayes factors to compare
models (or hypotheses), ultimately resulting in posterior odds
for a model of association for each individual SNP (Equation
1, Y is data). p(H1|Y)/p(H0|Y) = [p(Y|H1)/p(Y|H0)] x
[p(H1)/p(H0)](1)Posterior Odds of H1 = Bayes factor x Prior
Odds of H1Unlike the p-value approach to testing for
association, the Bayes factor does not require a multiple
testing correction. Instead, meaningful prior information in the
form of prior odds of association can be incorporated. This
prior information depends on the number of SNPs expected to
be disease variants (or in LD with disease variants), not on the
number of SNPs genotyped or on the number of tests carried
out. We explore the Bayes factor approach using both
simulated and real trio datasets.

259 PHENOMIC ANALYSIS OF PSYCHIATRIC
SYMPTOMS AND RATING SCALES IN PARKINSON’S
DISEASE
R. Schork* (1), M. Houser (2), C. Bloss (1), N. Schork (3)
1. Scripps Genomic Medicine; Elon University 2. Division of
Neurology, Scripps Clinic 3. Department of Molecular and
Experimental Medicine, The Scripps Research Institute
*rschork@elon.edu
Non-motor symptoms in Parkinson’s disease (PD) are
common, but poorly understood. One issue is a paucity of
research in this area, and another is evidence that traditional
analysis of total scores on standard psychiatric rating scales
may be inadequate for assessment of these symptoms (e.g.,
anxiety) in PD. As such, we conducted association analysis of
psychiatric symptoms in PD, comparing findings from
analysis of total rating scale scores versus item-level profiles.
Four scales administered to 23 PD patients were evaluated,
including the State-Trait Anxiety Inventory, Geriatric
Depression Scale, Beck Depression Inventory, and Marin
Apathy Scale. Independent variables (IVs) hypothesized to be
associated with psychiatric symptomatology were identified
from the literature, and two sets of analyses were performed:
(1) linear regression of total scores for each scale on each IV;
and (2) multivariate distance matrix regression (MDMR) of
item-level profiles on each IV. Fourteen IVs were identified,
including demographic and disease-related variables,
cognitive indices, daytime sleepiness, and comorbid disease.
Results revealed differences in the IVs found to be associated
with total scores versus item-level profiles on each of the four
scales. Across all of the scales, IVs with the most discrepant
association statistics between the two methods included
daytime sleepiness, Mini-Mental Status, and perceived
memory problems. Furthermore, follow-up analyses suggest
that certain items on each scale may be more salient than
others for psychiatric assessment in PD populations. Findings
suggest that item-level “phenomic” analysis of psychiatric
rating scales may provide useful additional information in the
assessment of psychiatric symptomatology in PD.
260 BLOCK-WISE GENOME-WIDE ASSOCIATION
ANALYSIS IDENTIFIES A LIMITED NUMBER OF
REPLICABLE CANDIDATE REGIONS LINKED WITH
SCHIZOPHRENIA
T. Gladwin (1), E. Derks* (1), W. Cahn (1), R. Kahn (1), R.
Ophoff (1)
1. Department of Psychiatry, Rudolf Magnus Institute of
Neuroscience, University Medical Centre Utrecht, Utrecht,
The Netherlands
*e.m.derks@umcutrecht.nl
Schizophrenia is a complex disorder with high heritability.
Genome Wide Association (GWA) studies have been hindered
by low statistical power to detect risk alleles with small effect
sizes. We will introduce a new approach to the analysis of
GWA data. Genotypic data were available for 728 cases and
653 controls from the Netherlands; GAIN data of 1,172 cases
and 1,378 were used for replication. The aim is to identify
regions with a significantly increased number of nominally
significant tests. To this end, 22 autosomal chromosomes were
split into 1390 2 MB regions. While single SNP and haplotype
analyses did not result in statistically significant findings, we
identified 13 regions with an increase in nominally significant
SNPs. Five of these regions could be replicated (p

261 POWER DIFFERENCES FOR FAMILY-BASED
EPISTASIS DETECTION METHODS
S. Bergen* (1), A. Fanous (2), K. Kendler (3), B. Maher (4)
1. Department of Human and Molecular Genetics, Virginia
Commonwealth University 2. Washington VA Medical
Center, Georgetown University Medical Center, Virginia
Commonwealth University 3. Virginia Institute for Psychiatric
and Behavrioral Genetics, Department of Psychiatry, Virginia
Commonwealth University 4. Departments of Psychiatry and
Human and Molecular Genetics, Virginia Commonwealth
University
*sbergen@gmail.com
The impact of genetic variation on common diseases is
complex, involving many loci and their interactions. In
population-based association samples, modeling gene-gene
interaction, or epistasis, the conditional impact of one genetic
polymorphism on another, is a relatively straightforward
exercise. In these samples, genotypes at multiple loci, with
their interaction term(s), can be included in a regression model
as predictors. Detection of gene-gene interactions in
family-based association samples is more complicated, but
several methods have been proposed. In these approaches
pseudocontrols are created based on the alleles or genotypes
that were not transmitted to an affected offspring from
genotyped parents. Two main approaches to generating
pseudocontrols involve using nontransmitted two-locus
genotypes (Cordell approach) and nontransmitted alleles
(two-locus haplotype relative risk approach; HRR). In the
former, 15 pseudocontrols would be generated, while the latter
yields only three. These cases and pseudocontrols are then
analyzed using logistic regression conditional on the parental
genotypes. The core distinction between these approaches is
the inclusion of transmitted alleles in the creation of
pseudocontrol genotypes in the Cordell approach. We have
explored the power for both of these methods under a variety
of models of epistasis in 1000 simulated samples of 500
parent-child trios. Under “classic” epistasis models, the HRR
approach yields greater power, but under most other models
(recessive, additive, heterogeneity, and crossover) the Cordell
approach demonstrates increased power for detecting epistasis.
These results suggest different approaches to family based
epistasis testing are indicated depending on the expected
model of epistasis in effect.
262 PSYCHIATRIC GWAS CONSORTIUM -
CHALLENGES IN WORLD WIDE GENETIC
ASSOCIATION STUDIES
S. Ripke* (1), M. Daly (1), B. Neale (1)
1. CHGR
* ripke@chgr.mgh.harvard.edu
Here we present a quality control pipeline for genome-wide
association SNP data. This pipeline was developed at MGH in
Boston, as a direct outgrowth of the Psychiatric GWAS
Consortium Analytic Committee. The aims of this pipeline are
to execute the quality control of GWAS-SNP data, impute
variation based on a reference sample and combine the data in
a single analysis. The quality control steps include the
capacity to identify relatives and overlapping samples in and
across studies, as well as produce principal components
representing population variation to control for stratification in
downstream-analysis and ancestry outlier exclusion. Through
the use of parallelization and massive computer clusters such
as the GCC (Netherlands), preliminary results can be
generated in as little as one week, even for study sizes of over
40,000 individuals. This poster is meant as an addition to the
Plenary Session 4 – Psychiatric GWAS Consortium on
Sunday, November 8th, and should educate the field about the
challenges from handling multiple datasets from all over the
world, as well as provide insight into emerging solutions to
these difficulties.

263 EVIDENCE FOR EPISTASIS IN GENOME-WIDE
ASSOCIATION STUDIES OF BIPOLAR DISORDER
J. Judy* (1), P. Belmonte (1), F. Seifuddin (1), M. Pirooznia
(1), Bipolar Genome Study (BiGS), J. Potash (1), P. Zandi (1)
1. Johns Hopkins School of Medicine, Johns Hopkins School
of Public Health
* jtoolan1@jhmi.edu
Bipolar Disorder (BD) is highly heritable, suggesting an
underlying genetic etiology. However, efforts to identify
causal genetic variants in BD have been markedly
unsuccessful. Epistasis, whereby a genetic variant at one locus
influences the phenotypic effect of a different locus, may
contribute to this lack of discovery. Data from large scale
genome-wide association studies (GWAS) affords researchers
the opportunity to explore this phenomenon. We examined the
potential role of epistasis in BD by analyzing data from two
GWAS from the BiGS Consortium: an initial sample of 1001
cases and 1034 controls from the GAIN data, and a follow-up
sample of 1199 cases and 403 controls from the TGEN data.
We used PLINK to search for statistically significant pairwise
interactions, followed by querying functional annotation
databases to find evidence for biological interactions. We
followed two complementary strategies. We first employed
the “clumping” routine to identify the 513 most significantly
associated loci that tagged the remaining SNPs, and tested for
interactions between them. We then examined the pairwise
interactions between SNPs in ANK3, which has been
implicated as genome-wide significant in BD, and SNPs
across the genome. The most significant interaction consistent
between the two samples was between rs4948254 in ANK3
and 3 SNPs (rs2206135, rs2235460, and rs4811247) in
CTNNBL1 (p-values between 10e-03 to 10e-05).
Interestingly, CTNNBL1 is a homologue to beta-catenin, a
key component of the Wnt signaling pathway, and is involved
in apoptosis. We plan to test for replication of this interaction
using the WTCCC data.
264 GENOME WIDE STRATEGIES TO CORRECT
FOR MULTIPLE TESTING IN THE STUDY OF
GENETIC INTERACTIONS
G. Guffanti* (1), H. Stern (1), J. Turner (1), S. Potkin (1), F.
Macciardi (1), N. Schork (2)
1. University of California, Irvine 2. Scripps Health and The
Scripps Research Institute
*gguffant@uci.edu
Success in identifying susceptibility genes for complex traits
is strongly affected by the ability to describe the effects of
gene-environment (GxE) interactions. We present a
comprehensive genome-wide strategy to test GxE interactions
through an integrated methodological framework. This
methodology performs iterative resampling procedures for
interaction terms to correct for multiple comparisons. Our
methodology tests separately tests GxE interaction effects
from the main effects using the traditional regression-based
general linear models (GLMs). We isolate the proportion of
variance explained by the interaction term factoring out main
effects from the GLM that tests the hypothesis of no
interaction. Then we apply non-parametric inferential
data-driven procedures to the variance explained by the
interaction and contrast the results with
null-quantile-transformed distribution. The rejection regions
for the test statistics are defined using stepwise multiple
testing procedures to derive the appropriate adjustment of the
p-values. We evaluated the accuracy of the multiple testing
corrections in both simulation and real dataset studies
assessing effect size, power and sample size. We validated our
novel measure to describe GxE interactions’ effects on disease
risk by contrasting the E+,BB events that identify the high risk
profile subjects to the rest of the individuals involved in the
study, the negative risk profile subjects. This is the first
statistical approach that recasts the relationship between the
four main components of statistical hypothesis testing (i.e.,
significance level α, power, effect size, sample size) so that it
can account for the specific characteristics of a complex
phenomenon like GxE interaction.

265 MODELING THE COMBINED EFFECTS OF SNPS
USING BINOMIAL LOGISTIC REGRESSION:
SELECTION CRITERIA AND THE USE OF
PRINCIPAL COMPONENTS ANALYSIS
T. Gladwin (1), W. Cahn (1), R. Kahn (1), R. Ophoff (1), E.
Derks* (1)
1. Department of Psychiatry, Rudolf Magnus Institute of
Neuroscience, University Medical Centre Utrecht, Utrecht,
The Netherlands
*e.m.derks@umcutrecht.nl
Genome Wide Association (GWA) studies suggest that many
loci with small effect sizes play a role in schizophrenia. We
present the results of a modeling approach that combines these
effects. Genome wide data were available for 728 cases and
653 controls. Principal component analysis was performed on
1618 SNP-variabless which were associated (P

267 SZGR: A COMPREHENSIVE SCHIZOPHRENIA
GENE RESOURCE
P. Jia* (1), J. Sun (1), A. Guo (2), Z. Zhao (1)
1. Vanderbilt University 2. Virginia Institute for Psychiatric
and Behavioral Genetics, Virginia Commonwealth University
*peilin.jia@vanderbilt.edu
Introduction: We have seen during the past two decades an
exponential growth of vast amounts of biological data in
schizophrenia genetics, including those generated by
traditional positional cloning approach, individual
gene/marker association studies and emerging genome-wide
association studies, more than 32 genome-wide linkage scans
and several meta-analyses, and a large number of microarray
experiments. Besides these genetic datasets, abundant
biological information for the schizophrenia candidate genes
can be extracted from public databases such as Gene Ontology
annotations, protein-protein interaction (PPI) networks, and
regulatory and cellular pathways. At present, there is a strong
trend towards integrating the data from various genetic studies
and their related biological information in the cellular systems
so that promising candidate genes can be prioritized for follow
up bioinformatics analysis and experimental verification.
Methods: We designed and implemented Schizophrenia Gene
Resource (SZGR), a comprehensive database with
user-friendly web interface. SZGR was implemented as a
relational database using the open source MySQL database
system and is freely accessible through a web interface
developed in JSP technology. Results: SZGR deposits genetic
data from all available sources including association studies,
linkage scans, gene expression, literature, Gene Ontology
(GO) annotations, gene networks, cellular and regulatory
pathways, and microRNAs and their target sites. Moreover,
SZGR provides online tools for data browse and search, data
integration, custom gene ranking, and graphical presentation.
Conclusions: To our understanding, SZGR is the most
comprehensive resource for schizophrenia, or such kind in
psychiatric genetics. This system can be easily applied to other
complex diseases, especially other psychiatric disorders. The
SZGR database is available at
http://bioinfo.mc.vanderbilt.edu/SZGR/.

SUBSTANCE ABUSE
268 ASSOCIATION BETWEEN THE NMDA
RECEPTOR SUBUNIT 2B GENE (GRIN2B) AND
NICOTINE DEPENDENCE IN A SAMPLE OF
JAPANESE WORKERS
S. Sakata* (1), T. Shinkai (1), H. Chen (2), K. Utsunomiya
(1), Y. Fukunaka (1), K. Yamada (1), O. Ohmori (1), J.
Nakamura (1)
1. Department of Psychiatry, School of Medicine, University
of Occupational and Environmental Health, Kitakyushu, Japan
2. Department of Psychiatry, School of Medicine, University
of Occupational and Environmental Health, Kitakyushu,
Japan; Department of Public Health, Kaohsiung Medical
University, Kaohsiung, Taiwan
*bossnokobun@yahoo.co.jp
Preclinical research findings in laboratory animals indicate
that the glutamatergic system may be involved in nicotine
dependence. In animals, N-methyl-D-aspartate (NMDA)
receptor antagonists decreased nicotine self-administration or
reinstatement of nicotine-seeking behavior. NMDA receptor
dysfunction may be involved in the pathophysiology of
smoking behavior. The human gene cording for the 2B subunit
of the NMDA receptor (GRIN2B) is thus considered a
candidate gene for nicotine dependence. To examine the
hypothesis, we examined the association between smoking
behavior and three GRIN2B polymorphisms, G-200T
(5'UTR), C2664T (exon 13) and T5072G (3'UTR), using a
sample of Japanese healthy workers (N = 673). This study
was approved by the Ethics Committee of the University of
Occupational and Environmental Health, and informed
consent was obtained from all subjects prior to participation to
the study. Among smokers, the -200G allele, which has been
associated with lower gene activity, was associated with
having smoking cessation histories (for more than 1 month)
with non-significant trend (P=0.09). Our results suggest that
GRIN2B G-200T polymorphism may play a role in smoking
cessation in our sample. Details of association analyses for
other markers as well as marker haplotypes will be presented.
269 POSSIBLE ASSOCIATION BETWEEN THE
ALA72SER POLYMORPHISM OF THE
CATECHOL-O-METHYL TRANSFERASE GENE
(COMT) AND NICOTINE DEPENDENCE IN A
SAMPLE OF JAPANESE WORKERS
K. Utsunomiya* (1), T. Shinkai (2), S. Sakata (3), H. Chen
(4), Y. Fukunaka (5), K. Yamada (6), O. Ohmori (7), J.
Nakamura (8)
1. Department of Psychiatry, School of Medicine, University
of Occupational and Environmental Health
*k-utsu@med.uoeh-u.ac.jp
Catechol-O-methyl transferase gene (COMT) is one of the
enzymes involved in the degradation and inactivation of
catecholamine transmitters including dopamine, which is
present in dopaminergic brain regions. Nicotine stimulates
dopamine release and activates dopaminergic reward neurons.
The dopaminergic reward system may be a key mechanism in
nicotine dependence. Recently, new functional single
nucleotide polymorphism (SNP) Ala72Ser in the COMT gene,
which accounts for the enzyme activity, was found. The
purpose of our study is to examine the association between the
COMT Ala72Ser polymorphism and nicotine dependence in
its each stage (e.g., smoking initiation, dependence
development, and smoking cessation). Smoking status was
confirmed by in-person structured interviews. We have
recruited the present sample from one of the Japanese major
manufacturing company, with advantage of relatively
homogenous background (total N = 673). Among them, we
defined 435 smoking initiators (SI) and 234 non-initiators
(who reported never having smoked a single cigarette: NI).
Among SI, 417 were high nicotine dependent smokers (who
reported having smoked > 100 cigarettes or total smoking
duration > 6 months in their lifetime: HND), and 16 low
nicotine dependent smokers (LND). Although there was no
significant difference in both genotype and allele frequencies
between SI and NI, we found a significant difference in both
genotype (chi-square= 13.56, d.f. = 2, p= 0.019) and allele
frequencies (chi-square = 5.089, d.f. = 1, p = 0.038, OR =
0.34, 95%CI = 0.14-0.81) of the COMT Ala72Ser between
HND and LND. These data suggest that the COMT Ala72Ser
polymorphism is possibly associated with the degree of
nicotine dependence in Japanese workers.

270 THE ASSOCIATION OF NEURONAL NICOTINE
ACETYLCHOLINE RECEPTOR ALPHA4 AND BETA2
GENE POLYMORPHISMS WITH NICOTINE
DEPENDENCE IN JAPANESE MALE WORKERS
H. Chen* (1), T. Shinkai (2), S. Sakata (2), K. Utsunomiya
(3), Y. Fukunaka (2), K. Yamada (2), O. Ohmori (4), J.
Nakamura (2)
1. Department of Psychiatry, University of Occupational and
Environmental Health, Kitakyushu, Japan; Department of
Public Health, Kaohsiung Medical University, Kaohsiung,
Taiwan 2. Department of Psychiatry, University of
Occupational and Environmental Health, Kitakyushu, Japan
3. Department of Psychiatry, University of Occupational and
Environmental Health, Kitakyushu, Japan; Health
Management Department, Shimonoseki Shipyard &
Machinery Works, Mitsubishi Heavy Industries, Ltd.,
Shimonoseki, Japan 4. Department of Psychiatry, University
of Occupational and Environmental Health, Kitakyushu,
Japan; Wakato Hospital, Kitakyushu, Japan
*stbchen@med.uoeh-u.ac.jp
Polymorphisms in the genes coding the nicotinic acetylcholine
receptors have been suggested to play a role in the
determination of smoking-related phenotypes because
smoking activates the brain reward system through these
receptors. To examine this hypothesis, we conducted a
genetic association study in a well-defined sample of Japanese
workers (N =673). We analyzed 5 SNPs in the CHRNA4
gene and 3 SNPs in the CHRNB2. We assessed nicotine
dependence using the Fagerström Test of Nicotine
Dependence (FTND) and the Tobacco Dependence Screener
(TDS). Among 284 current male smokers, 168 were
dependent smokers (DS) (FTND score 4 or more) and 116
were non-dependent smokers (non-DS). We found a
significant difference of the CHRNA4 (rs1044397) genotype
distribution between DS and non-DS (chi-square= 7.84, df =
2, p-value = 0.02). As for the CHRNB2 gene polymorphism
(rs4845652), we found non-significant differences in both
genotype (chi-square =2.99, df=1, p-value=0.08) and allele
frequencies (chi-square=3.78, df=1, p-value=0.05) between
DS and non-DS groups. Our data suggests that CHRNA4 and
CHRNB2 gene may correlate to nicotine dependence in our
sample. The gene-gene interaction data will be presented.
271 ASSOCIATION OF POLYMORPHISM IN THE
HUMAN MU-OPIOID RECEPTOR OPRM1 GENE
WITH NICOTINE DEPENDENCE IN JAPANESE
WORKERS
T. Shinkai* (1)
1. Department of Psychiatry, University of Occupational and
Environmental Health, Kitakyushu, Japan
*shinkai@med.uoeh-u.ac.jp
The mu-opioid receptor has been implicated in the
pathogenesis of substance dependence including nicotine
dependence. Studies examining the association of the
mu-opioid receptor gene (OPRM1) with substance
dependence have focused on the Asn40Asp (A118G) single
nucleotide polymorphism (SNP). In the present study, we
tested association between the functional OPRM1 A118G
polymorphism (rs1799971) and nicotine dependence in its
each stage (e.g., smoking initiation, dependence development,
and smoking cessation) in a well-defined sample of Japanese
workers. We have recruited the present sample from one of the
Japanese major manufacturing company (total N = 673), with
advantage of relatively homogeneous background. Smoking
status was confirmed by in-person structured interviews.
Among our sample, we identified 233 never smokers (who
reported never having smoked a single cigarette in their
lifetime) and 167 heavy smokers (who smoke >20 cigarettes
daily). We found a non-significant difference in allele
frequency (?2 = 3.54, df = 1, p = 0.06) between never smokers
and heavy smokers. Our data suggests that OPRM1 gene may
confer the risk for nicotine dependence in our sample.

272 ASSOCIATION BETWEEN THE BDNF VAL66MET
POLYMORPHISM AND NICOTINE DEPENDENCE IN
A SAMPLE OF JAPANESE WORKER
K. Yamada* (1), T. Shinkai (1), K. Utsunomiya (2), H. Chen
(3), S. Sakata (1), Y. Fukunaka (1), O. Ohmori (4), J.
Nakamura (1)
1. Department of Psychiatry, School of Medicine, University
of Occupational and Environmental Health, Kitakyushu, Japan
2. Department of Psychiatry, School of Medicine, University
of Occupational and Environmental Health, Kitakyushu,
Japan; Health Management Department, Shimonoseki
Shipyard & Machinery Works, Mitsubishi Heavy Industries,
Ltd., Shimonoseki, Japan 3. Department of Psychiatry, School
of Medicine, University of Occupational and Environmental
Health, Kitakyushu, Japan; Department of Public Health,
Kaohsiung Medical University, Kaohsiung , Taiwan
4. Department of Psychiatry, School of Medicine, University
of Occupational and Environmental Health, Kitakyushu,
Japan; Wakato Hospital, Wakamatsu-ku, Kitakyushu, Japan
*hokuto_no_ken_1225@yahoo.co.jp
Brain-derived neurotrophic factor (BDNF) is a nerve growth
factor that plays an important role in the development and
maintenance of adult neurons and is important regulator of
synaptic plasticity in human brain. It has been reported that
BDNF and dopamine (DA) systems interact within a number
of neurobiological processes (Guillin et al., 2001). BDNF's
influence on DA responsiveness might be an important factor
in the etiopathology of substance abuse including nicotine
dependence, which is implicated in DA reward system
(Guillin et al., 2001, 2007). Interestingly, preclinical data
show that acute administration decreases, whereas chronic
nicotine increases, BDNF mRNA levels in the hippocampus
(Kenny et al., 2000). Further, genome-wide linkage scans
indicate that the region of chromosome 11p13, where the
BDNF gene is located, likely harbors susceptibility genes for
nicotine dependence (Li et al., 2003). Moreover, Beuten et al.
(2005) provide evidence of an association between allelic
variants of BDNF and nicotine dependence in male Caucasian
smokers (Beuten et al., 2005). More recent reports also
showed an association between smoking behavior and the
BDNF Val66Met polymorphism (Lang et al., 2007). Taken
together, these findings suggest that BDNF may play an
important role in the pathophysiology of nicotine dependence.
We have recruited the present sample from one of the
Japanese major manufacturing companies (total N = 673),
with advantage of relatively homogeneous background.
Among our sample, we identified 233 never smokers (who
reported never having smoked a single cigarette in their
lifetime) and 167 heavy smokers (who smoke ?20 cigarettes
daily). We could not find an association between smoking and
the BDNF Val66Met polymorphism in our sample. Our data
suggests that BDNF gene may not confer the risk for nicotine
dependence in Japanese workers.
273 PRINCIPAL COMPONENT AND BAYESIAN
NETWORK ANALYSES OF GENOME WIDE
ASSOCIATION RESULTS FROM SUBSTANCE
DEPENDENCE AND SMOKING CESSATION
SUCCESS.
T. Drgon* (1), C. Johnson (1), J. Rose (2), G. Uhl (1)
1. NIDA, NIH 2. Duke University
*tdrgon@intra.nida.nih.gov
Complex traits with polygenic genetic architecture provide
challenges for genome wide association. When expected effect
sizes for individual polymorphisms are modest, extremely
large sample sizes may be required to achieve “genome wide
significance” using eg 2 tests with corrections for multiple
comparisons. Principal Component Analysis (PCA) reduces
multidimensional datasets to simpler covariance or distance
matrices and is a priori agnostic to structure in the data. PCA
components readily distinguish individuals of different
racial/ethnic backgrounds, as we have demonstrated in
comparison of 500k GWA data from f European American,
African American and Asian samples. However, other
principal components clearly distinguish samples of substance
dependent individuals from controls, and successful vs.
unsuccessful quitters in smoking cessation trials. We have
developed permutation and Monte Carlo tests that allow us to
assign p values for the significance of these differences.
Bayesian networks (BN) provide probabilistic graphical
models that help visualize a set of variables and their
conditional independencies. Bayesian networks can thus help
us to classify individuals based on genotypes and other
relevant phenotypic variables. We have constructed Bayesian
network models for predicting success in smoking. Each of
these models provides support for the idea that additive
genetic influences can describe substantial proportions of the
genetic contributions to these phenotypes. Each of these
models is internally consistent and provides a basis for
development of clinically relevant probabilistic decision
making.

274 TYROSINE HYDROXYLASE GENE AND
METHAMPHETAMINE USE DISORDERS
H. Ujike* (1), Y. Okahisa (1), M. Takaki (1), M. Kodama (1),
T. Inada (2), N. Uchimura (2), M. Yamada (2), M. Iyo (2), I.
Sora (2), N. Iwata (10), N. Ozaki (2)
1. Department of Neuropsychiatry, Okayama University
Graduate School of Medicine, Dentistry and Pharmaceutical
Sciences 2. JGIDA
* hujike@cc.okayama-u.ac.jp
Tyrosine hydroxylase (TH) is a rate-limiting enzyme of
dopamine synthesis and may be involved in several
dopamine-related neuropsychiatric disorders including
substance dependence and schizophrenia. Previous reports
showed significant genetic association between the TH gene
and nicotine dependence and alcoholism. We examined two
polymorphisms of the TH gene, HUMTH01-VNTR and
Val81Met (rs6356), in 221 patients with methamphetamine
dependence and/or psychosis and 279 age- and sex-matched
healthy controls. There was no significant difference in allelic
and genotypic distribution of HUMTH01-VNTR and
Val81Met between methamphetamine dependence/psychosis
and control. Several clinical phenotypes of methamphetamine
dependence/psychosis, such as age at first abuse, duration of
latency from the first abuse to onset of psychosis, prognosis of
psychosis after therapy, and complication of spontaneous
relapse of psychotic state were examined, however, there was
no association between any polymorphism and the clinical
phenotype, either. HUMTH01-VNTR is a tetra-nucleotide
repeat located in the intron 1, which motif indicates binding to
transcription factors. K1 allele of HUMTH01-VNTR was
shown to be associated with heart rate and HVA concentration
in CSF and serum. Val81Met polymorphism changes TH
structure. Accordingly, the two polymorphisms examined in
the present study may be physiologically functional.
Therefore, the present findings may indicate that individual
variation of TH activity may not be involved in susceptibility
to methamphetamine use disorders and those clinical severity
or prognosis of psychosis.
275 LINKAGE SCAN OF NICOTINE DEPENDENCE IN
THE UCSF FAMILY ALCOHOLISM STUDY
I. Gizer* (1), C. Ehlers (2), C. Vietan (3), K. Seaton-Smith
(4), H. Feiler (5), J. Lee (6), S. Segall (7), D. Gilder (1), K.
Wilhelmsen (1)
1. University of North Carolina 2. Scripps Research Institute
3. California Pacific Medical Center 4. Arizona College of
Osteopathic Medicine 5. University of California at San
Francisco 6. University of Illinois at Urbana-Champaign
7. University of North Carolina at Chapel Hill
* igizer@unc.edu
Ample data suggest nicotine dependence represents a heritable
condition, and several research groups have performed linkage
analysis to identify genomic regions associated with this
disorder. In the present study, a genome-wide linkage scan for
nicotine dependence was conducted in a community sample
that included 950 probands and 1204 first-degree relatives
recruited as part of the UCSF Family Alcoholism Study. The
Semi-Structured Assessment for the Genetics of Alcoholism
(SSAGA) was used to derive DSM-IV nicotine dependence
diagnoses, and linkage analysis was conducted using variance
components analysis. The strongest linkage signal was
observed on chromosome 2q31.1 at 184 centimorgans nearest
to marker D2S2188 (LOD score = 3.52, nominal p-value =
.00005). Additionally, suggestive linkage peaks were
identified on chromosomes 2q13, 4p15.33-31, 11q25, and
12p11.23-21. Notably, analyses of co-occurring alcohol
dependence suggested that the 2q31.1 locus is not linked to
alcohol dependence in the present population, and thus may
influence nicotine dependence specifically. In addition,
linkage analysis of the 14 individual nicotine dependence
symptoms assessed by the SSAGA to the 2q31.1 locus showed
that a broad range of nicotine dependence symptoms provided
modest contributions to the observed linkage signal suggesting
that this locus confers a general risk towards nicotine
dependence rather than influencing a specific facet of the
disorder. In sum, these data provide compelling evidence that
chromosome 2q31.1 harbors a susceptibility locus for nicotine
dependence.

276 ASSOCIATION ANALYSIS BETWEEN
POLYMORPHISMS IN MONOAMINE OXIDASE A
(MAOA) AND DOPAMINE RECETOR D2 (DRD2)
GENES AND COCAINE DEPENDENCE
A. Negrão* (1), A. Pereira (2), R. Laranjeira (3), J. Krieger
(2), H. Vallada (1)
1. Program of Genetics and Pharmacogenetics, Department
and Institute of Psychiatry, University of São Paulo Medical
School, São Paulo, Brazil 2. Laboratory of Genetic and
Molecular Cardiology/LIM-13, Heart Institute (InCor),
University of São Paulo Medical School, São Paulo, Brazil 3.
Alcohol and Drug Research Unit, Psychiatry Department,
Federal University of São Paulo, São Paulo, Brazil
*abnegrao@usp.br
Dopaminergic brain systems have a major role in drug reward,
thus making genes involved in these circuits candidates for
susceptibility to substance use disorders. An association
between cocaine dependence and a dopamine transporter gene
in a sample of cocaine users in Brazil has previously been
published. In the present study we investigate other candidate
genes involved in dopaminergic neurotransmission in that
same sample: monoamine oxidase A (MAOA) and dopamine
D2 receptor (DRD2). MAOA is an enzyme involved in the
oxidative metabolism of dopamine. Antisocial behavior
associated with alcohol consumption has been related to a
variation in the MAOA gene. In addition, epidemiological
evidence demonstrated a high association between antisocial
behavior and substance dependence. Therefore, MAOA gene
polymorphism could be linked to substance dependence but no
study has documented its association to cocaine dependence to
date. Polymorphisms at the DRD2 have been reported in many
alcohol-dependent studies. 681 patients who met ICD10
diagnosis of cocaine dependence and 756 controls were
genotyped for three SNPs in the MAOA gene (rs 6323, rs
2235185, rs 1137070), one SNP (rs1801028) and one
insertion/deletion polymorphism (rs 1799732) in the DRD2
gene. We observed no significant differences in allele,
genotype, or haplotype frequencies between cases and controls
for any of the tested markers. Our study suggests that there is
no association between variants in the MAOA and DRD2
genes and cocaine dependence.
277 GENETIC EPIDEMIOLOGY OF OPIOID
DEPENDENCE IN BULGARIA
A. Todorov* (1), M. Lynskey (1), M. Nikolov (2), O.
Beltcheva (2), R. Kaneva (2), I. Kremensky (2), D.
Krasteva (3), E. Nesheva (3), E. Yankova (4)
1. Washington Univ. Saint Louis 2. Molecular Medicine
Center, Sofia, Bulgaria 3. Bulgarian Addictions Institute
4. Initiative for Health Foundation
*todorov@wustl.edu
This ongoing study of heroin dependence in Bulgaria is
collecting semi-structured psychiatric assessments and blood
samples from 2,500 injecting drug users 18 years and older
who have used heroin regularly for more than one year. We
present the study methodology and preliminary findings from
the first ~ 1,500 participants. Briefly, 62% of participants
agreed to an HIV test with 2.5% of samples testing positive
(24 of 959) – higher than previous reports for Bulgaria.
Preliminary genotyping is complete for ~1,100 cases and
~1,100 matched controls; for SNPs in OPRM1, DRD2, CRH,
COMT, BDNF, SLC6A4, TPH2 and CLOCK. Controls were
drawn from the population-representative repository at the
National Genetics Laboratory. In OPRM1, we find no
evidence for association with either A118G (rs1799971) or
with rs2075572 (both p > 0.50); but a possible association
with rs932245 in intron 1 (p < 0.01). In other genes, possible
associations include rs3176921, upstream of CRH and in
linkage disequilibrium with a block spanning the CRH coding
region (p < 0.01); and with the Val66Met polymorphisms in
BDNF (p = 0.03).Funded by DA018823.

278 ASSOCIATION ANALYSIS BETWEEN
POLYMORPHISMS IN THE
BUTYRYLCHOLINESTERASE (BCHE) GENE AND
COCAINE DEPENDENCE
A. Negrão* (1), A. Pereira (2), R. Laranjeira (3), J. Krieger
(2), H. Vallada (1)
1. Program of Genetics and Pharmacogenetics, Department
and Institute of Psychiatry, University of São Paulo Medical
School, São Paulo, Brazil 2. Laboratory of Genetic and
Molecular Cardiology/LIM-13, Heart Institute (InCor),
University of São Paulo Medical School, São Paulo, Brazil
3. Alcohol and Drug Research Unit, Psychiatry Department,
Federal University of São Paulo, São Paulo, Brazil
* abnegrao@usp.br
Genetic markers in the dopaminergic brain systems are
associated with drug dependence but other biological
pathways can contribute to the susceptibility to this disorder.
Butyrylcholinesterase (BChE) is codified by the BChE gene
and it hydrolyzes cocaine to metabolites with little biologic
activity. Point mutations in the BChE gene have been
described in the general population; some of them being
“silent” mutations. BChE has also been tested as a novel
therapeutic agent for cocaine dependence. Brimijoin et al,
2008 demonstrated that a quadruple mutant hydrolase derived
from human butyrylcholinesterase suppressed cocaine toxicity
and abolished drug-primed reinstatement in rats.
Polymorphisms in the BChE gene can lead to different
enzyme profiles generating individuals with
increased/decreased susceptibility to engage in addictive
behaviors due to varying concentrations of cocaine reaching
the reward system in the brain. In this study we hypothesize
that genetic variations in the BChE gene can be risk factos for
cocaine dependence. 681 patients who met ICD10 diagnosis of
cocaine dependence and 756 controls were genotyped for
three SNPs in the BChE gene (rs1803274, rs4263329,
rs4680662). All markers were in HWE. Genotype differed
significantly for rs4263329 between cases (f(GG)=0,6%) and
controls (f(GG)=1,4%), (p=0.03; ?2=4,48). Genotypes from
the other two markers and allele frequencies did not differ
between cases and controls. No haplotypic effect was
detected. We suggest that the GG genotype in rs 4263329 can
be a protective factor for cocaine dependence. Additional
studies are required to elucidate the role of BChE in the
pathophysiology of cocaine dependence.
279 CHRM2 GENOMIC REGIONS DIFFERENTIALLY
ASSOCIATE WITH INTERNALIZING AND
EXTERNALIZING COMORBIDITIES IN ALCOHOL
DEPENDENT INDIVIDUALS
D. Kertes* (1), D. Dick (2), C. Prescott (3), K. Kendler (2), B.
Riley (2)
1. University of Florida 2. Virginia Commonwealth University
3. University of Southern California
*dkertes@gmail.com
Background: Genetic epidemiology studies in psychiatry have
demonstrated that genetic factors contribute to two broad sets
of behaviors: externalizing disorders and internalizing
disorders. The muscarinic acetylcholine receptor M2
(CHRM2) is one of several genes commonly studied for its
role in alcohol dependence which also show associations with
both internalizing and externalizing comorbidities in this
population. This research aims to identify whether CHRM2
loci differentially associate with comorbid internalizing and
externalizing phenotypes that commonly occur in alcohol
dependent individuals. Method: Lifetime history of major
depression (MD), conduct disorder (CD) and antisocial
personality disorder (ASPD) were ascertained via structured
clinical interviews in 552 alcohol dependent individuals. MD,
CD and ASPD symptom counts and diagnoses were associated
with allele frequencies in 20 CHRM2 markers via
regression-based analyses. Results: Results revealed
significant associations for five SNPs with CD symptoms, CD
diagnosis, and ASPD symptoms (.05>p>.001). Three SNPs
showed significant associations with MD symptoms or
diagnosis (.05>p>.01). Examination of LD structure revealed
that MD and CD/ASPD phenotypes were associated with
markers in different genomic regions that were consistent with
previous reports of association with externalizing and
internalizing phenotypes. Conclusions: Both MD and
CD/ASPD phenotypes in alcohol dependent individuals are
associated with SNP variants in CHRM2 and are distinctly
associated with different genomic regions of CHRM2. These
results suggest variants in different genomic regions in
CHRM2 predict liability to different comorbid conditions in
alcohol dependent individuals.

280 INTRONIC SNP FROM DRD2 GENE AND DRD2
HAPLOTYPES, ASSOCIATED WITH ALCOHOLISM
IN RUSSIANS
M. Monakhov* (1), T. Lezheiko (2), S. Borozdina (2), O.
Evdokimova (2), V. Golimbet (2)
1. Engelhardt Institute of Molecular Biology, Russian
Academy of Sciences, Moscow, Russia 2. Mental Health
Research Center, Russian Academy of Medical Sciences,
Moscow, Russia
* misha.monahov@gmail.com
Introduction: Dopamine receptor type 2 gene has long been
studied as a candidate for addictive behaviors, including
alcoholism. We present results of an association analysis of
alcoholism sample from Russian population. Five SNPs from
DRD2 as well asVal/Met COMT polymorphism were
investigated. Methods: Case sample consisted of 208 alcoholic
patients, diagnosed according to criteria of ICD-10.Data on
the amount of daily alcohol consumption, typical duration of
hard drinking periods and remission periods, parental age at
birth, tobacco smoking, life stress events were collected.
Control sample included 366 healthy volunteers with no
history of mental disorders. DRD2 polymorphisms rs1800498,
rs1801028, rs6275, rs6277, rs1800497 and COMTVal158Met
were analyzed. Genotyping was performed with 5’-nuclease
assay. Results and discussion: We have found an association
between alcoholism affection status and intronic SNP
rs1800498from DRD2 gene (chisq=5.53 df = 1 p=0.019) as
well as with haplotypes containingthis polymorphism (chisq=
17.03 df = 6 p=0.009). rs1800498 was also associated with
duration ofhard drinking periods (F(2, 173)=3.37, p=0.037).
Statistically significant result was found fora two-SNP
haplotype (rs1801028-rs1800497) and alcoholism in female
subsample (chisq= 11.7 df = 3 p=0.0085).These data, obtained
by the study of novel sample, add up to the pool of findings of
DRD2gene role in alcohol dependence. The same SNP is
associated with schizophreniaand altruistic behavior according
to our previous research that may point to its functional
effect.
281 NETWORK ANALYSIS OF CANDIDATE GENES
OF ALCOHOL CONSUMPTION
A. Lourdusamy* (1), G. Schumann (1)
1. Institute of Psychiatry, King's College London
* anbarasu.lourdusamy@kcl.ac.uk
Microarray analyses of brain gene expression in several rodent
models for excessive alcohol consumption have identified
candidate genes that underlie the genetic predisposition to
drink alcohol. Although the mechanism of these candidate
genes is being explored in human, little is known about the
molecular relationship between them. Here, we set out to
systematically analyze the complex effects of interrelated
genes and provide a framework for revealing their
relationships in association with alcohol consumption. The
alcohol network is composed of 29 human homologs of
proteins known to be involved in excessive alcohol
consumption in mice, and 183 additional human proteins that
interact with these human homolgos. Overall, the network
consists of 416 binary interactions among 212 unique proteins.
We observed that human protein-protein interaction networks
associated with alcohol consumption have a power-law
connectivity distribution as many other biological networks
have. These proteins are strongly interconnected and in turn
form 10 sub-networks which comprise over 50% of candidate
genes. Among candidate target genes associated with alcohol
consumption, the genes including, PTPN11, GNB1, PSMB7,
B2M, THRA, and GRIA1 have high connectivity (hubs). The
hub nodes and sub-networks are consistent with the prior
knowledge about alcohol consumption. In particular, PTPN11
appears to play a very important role in the alcohol network
through frequent interactions with key proteins in cellular
signaling. This network-based approach represents an
alternative method for analyzing the complex effects of
alcohol candidate genes.

282 DOPAMINE D4 RECEPTOR GENE: POSSIBLE
INFLUENCE ON ATTENTION DEFICIT
HYPERACTIVITY DISORDER IN BRAZILIAN
POPULATION
G.C. Akutagava-Martins (1), G. Ferraz (1), J.P. Genro (1), G.
Polanczyk (2), C. Zeni (3), M. Schmitz (3), LAP Rohde (3),
MH Hutz (1), T. Roman* (1)
1. Department of Genetics, Federal University of Rio Grande
do Sul, Brazil 2.Department of Psychology and Neuroscience,
Duke University, USA 3. Department of Psychiatry and Legal
Medicine, Federal University of Rio Grande do Sul, Brazil.
*troman29@yahoo.com.br
The dopamine D4 receptor gene (DRD4) is one of the most
investigated genes in Attention deficit/hyperactivity disorder
(ADHD) and has already been accepted as a susceptibility
gene. The aim of present study was to search for a possible
association between ADHD and the 120 bp tandem
duplication of promoter region, the SNPs -616C>G (rs747302)
and -521C>T (rs1800955) and the 48 bp VNTR of DRD4 gene
in a Brazilian sample composed by 488 ADHD children and
adolescents, diagnosed according to DSM-IV criteria, and
their biological parents. The 120 bp tandem duplication and
the 48 bp VNTR were genotyped by PCR, while the SNPs -
616C>G and -521C>T were genotyped by PCR-RFLP. The
possibility of linkage disequilibrium among the studied
polymorphisms was tested using MLocus software. The
hypothesis of association was verified using FBAT software.
There was no evidence of association between each
polymorphism and ADHD for the whole sample (P values
ranging from 0.200 to 0.974). However, when the analysis was
restricted to families where the proband presented the
combined type of the disorder, the VNTR 2R allele was
preferentially not transmited (P=0.033). Haplotype analyses
did not show any association (P values ranging from 0.063 to
0.977). The supposed protective effect of 2R allele observed
herein is intriguing. This result must be interpreted cautiously
and investigated through other approaches, as dimensional
analyses. It is also possible that the findings, divergent from
the literature, are due to DRD4 structural complexity, which
should be understood to better characterize its association with
ADHD.

AUTHOR INDEX

Aarts, Esther 2
Abeles, Michael 242
Åberg, Elin O9.1
Aberg, Karolina O2.6
Abou Jamra, Rami O12.2, 149
Abraham, Richard O17.1
Acheson, Ruth 6
Acierno, Ron 110
Adati, Naoki O1.4
Ades, AE 93
Adkins, Daniel E. O2.6, 23
Adolfsson, Rolf O7.3, 52, 122, 136
Affonseca-Bressan, 170
Rodrigo
Agan, Noelle 106
Agartz, Ingrid 53, 64
Aggen, Steven S16.7
Agrawal, Arpana S16.2, S16.3,
S16.4, S16.6,
S16.7
Ågren, Hans O10.1, O10.5
Ahmankhaniha,
Hamidreza
97
Ahn, Yong-Min 47
Aitchison, Katherine J S1.1, O1.3, O2.5,
O7.4, O11.1,
O15.2, 143, 164,
190
Akelai, A. O12.4
Akiskal, Hagop S14.2, O7.6
Akiyama, Tsuyoshi 177
Akula, Nirmala ECI 19, S14.4,
O2.2, O5.5, 127,
163
Alaerts, Maaike 52, 122
Alatrouny, Mohamed 243
Alblas, Margrieta 119
Albrecht, E 114
Albu, Crenguta 34
Albu, Dinu 34
Albus, M 245
Al-Chalabi, Ammar O17.1
Alda, Martin O9.4, 162
Aleksic, Branko 176, 209, 220,
221, 222
Alexander, Michael O9.2, 245
Alho, Hannu 189
Ali, Jeffrey 137
Aliev, Fazil S16.7, O16.2, 117
Alizadeh, Behrooz 81
Alkelai, A. 233
Allardyce, Judith O11.2
Allgulander, Christer 30
Alliey, Ney 180
Allin, Matthew 236
Almasy, Laura S12.4, S12.5,
S16.6, S16.7, ECI
13, ECI 18, 76
Alonso, Yolanda 248
Alphs, Larry 199
Als, Thomas D. O1.1
Althoff, Robert S8.1
Amankwa, Susan 236
Amann-Zalcenstein,
D.
O12.4
Ambler, Antony O9.7
Amdur, Richard ECI 3, 179, 223
Amin, Farooq 115
Amir, Nurmiati 57
Amstadter, Ananda 110
An, Seon-Sook O3.5
Anand, Sonia O10.2
Ancoli-Israel, Sonia 56
Andersen, Johan O8.1, 39
Andersson, Gerhard O3.1
Andreassen, Ole 53, 64
Andresen, Michael S10.2
Andriuskeviciute, 109
Irena
Angelo, Gary W. 71
Anjorin, Adebayo ECI 17, O2.1, 59,
156
Anney, Richard P4.6, 16, 21, 36,
48, 258
Anton, Eva S. 25
Arcos-Burgos,
Mauricio
O11.6
Ardau, Raffaella 162
Arias Vasquez,
Alejandro
O8.3
Arima, Kunimasa 66
Arinami, Tadao 215
Aristotle, Aristotle 191
Arnold, Paul S10.1, S10.4,
S10.5
Arranz, Maria 83
Aryee, Martin S2.2
Aschauer, Harald N. 152
Asherson, Philip 3, 9, 11, 24, 59
Athanasiu, Lavinia 53
Athie, Maria Carolina 75
Aukes, Maartje 81
Aulchenko, Yuri 147
Autism Genome 36
Project, The
Austin, Jehannine P2.2, 43, 107
Ayub, Muhammad ECI 15, 173
Azzam, Amin S10.6
Babatz, Timothy D. ECI 12
Bachner-Melman,
Rachel
91
Backlund, Lena O10.1, O10.5
Badner, Judith S2.3, S2.5, 98,
157, 180
Bailey, Julia 65
Bailey, Mark 45
Baji, Ildikó 50
Baker, Tim ECI 7
Bakken, Trygve 64
Bakker, Steven C. 227, 234
Balachandar,
218
Vellingiri
Balazic, Joze 49
Ballinger, Dennis O16.4
Banaschewski, Tobias 11
Bannasch, Danika 22
Bannen, Ryan 135
Bansal, Vikas S13.5
Barenboim, Maxim 252
Barichello, Tatiana 75
Barnes, Michael O1.3, O7.4, O11.1
Barr, Cathy O14.3, 50, 95,
171, 202
Barrett, Thomas 157
Barry, Edwina 4, 6, 10
Barth, Alexander 120
Bartling, Jürgen 174
Baruch, Kuti 126
Basmanav, F. Buket O8.2, O9.2
Bass, Nick J ECI 17, O2.1,
O17.1
Batra, Anil 197
Bayes, Monica 7, 8, 9
Beardsley, Patrick M. O2.6
Becker, Jessica 174
Beckmann, J.S. O12.4
Beevers, Christopher
G.
58
Behm, Frederique 183
Beitchman, Joseph 172
Bell, Maureen 208
Bellgrove, Mark 12, 84
Belmonte, Pamela S14.1, S14.3, 154,
157, 263
Belmonte-de-Abreu,
Paulo S.
14
Beltcheva, Olga 277
Benák, István 50
Ben-Asher, E. O12.4
Benson, Gary 135
Bergen, Andrew S13.2, S13.4,
S13.5, O16.4
Bergen, Sarah ECI 3, 223, 261
Bergstrom, Jan O3.1
Berlo, Jacques 140
Bernard, Lerer 206
Berner, Michael 197
Berrettini, Wade S13.1, S13.2,
S13.5, 138, 157
Berry, Erin M. S15.5
Bertolucci, Paulo 73
Bertram, David S6.3
Bertuzzi, Guilherme P. 14
Berwaerts, Joris 199
Besnyo, Márta 50
Bespalova, Irina N. 71
Bettecken, Thomas S1.4
Beveridge, Natalie S7.2
Bevilacqua, Laura O1.7
Bevova, Marianna S4.1, S4.5
Biechele, Travis S15.5
Bielsa, Anna 8
Bierut, Laura S16.1, S16.2,
S16.3, S16.4,
S16.5, S16.6,
S16.7, ECI 7, 138
Bigdeli, Tim ECI 3
Bilder, Robert 242
Bilkei-Gorzo, Andras O12.2, 120
Binder, Elisabeth B. S1.4, O2.5, O3.2,
O15.1, 30
Binder, Elke O2.5, O3.2
Bipolar Genome Study S9.4, S14.2,
(BiGS)
S14.3, O5.5, O7.5,
O7.6, O11.4, ECI
14, ECI 19, 127,
166, 263, 283
Birn, F. O6.2
Bishop, Jeffrey S11.3
Bishop, John S13.5
Bitter, István 234
Bizarro, Lisianne 24
Björk, Karl 92
Black, Donald W. 115

Blackwood, Douglas O1.1, O5.1, 208,
216, 237
Blangero, John S12.3, S12.4,
S12.5, ECI 13, 76,
240
Bleotu, Coralia 149
Bliziotes, Michael S11.4
Bloch, Paul J. 41
Bloss, Cinnamon S13.1, S13.2,
S13.5, 64, 157,
169, 259
Blum, Kenneth 182
Bochdanovits, Zoltan S4.1, S4.4, S4.5
Bockholt, H.Jeremy O6.2
Bogue, Molly 23
Boks, Marco O11.2
Bollen, Joseph 140
Bonaguro, Russell J. S3.5
Bonde, Jens Peter 39
Bondy, Brigitta S1.4
Bonsall, Robert 79
Boomsma, Dorret S4.5, S8.1, 114,
147
Boretti-Hummer,
Andrea
7, 9
Borgå Johansen, 18
Espen
Børglum, Anders D. O1.1, O8.1, 27,
39, 212, 214
Borozdina, Svetlana 280
Bosch, Rosa 7, 8, 9
Bousman, Chad S6.2, 213
Boyd, Simeon 22
Bozdagi, Ozlem O13.1
Bradley, Bekh 79
Bradshaw, John 6
Bradwejn, Jacques 178
Braff, David 207, 249
Brain, Ursula 43
Bramon, Elvira 83, 236
Brandt, John O2.4
Braverman, Eric 182
Bray, Nick 72, 253
Brayne, Carol O17.1
Breen, Gerome S7.1, O1.3, O7.4,
O11.1, O11.5,
O17.4, 143, 164,
170
Bremner, Rod 95
Brentani, Helena ECI 8
Breslau, Naomi S16.5, ECI 7
Breuer, Rene S14.3, S14.4,
O5.5, O8.2, O9.2,
119, 160
Briones Velasco,
Magdalena
ECI 5
Brizendine, Edward ECI 14
Brockschmidt, Felix 174
Brodkin, Edward S. 41
Brookes, Keeley 4, 10
Brotman, Melissa 163
Brouwer, Rachel M. 85
Brown, Sarah 208
Bruce, Heather 135
Bruder, Jennifer 174
Brueckl, Tanja O15.1, 100, 101
Bruining, Hilgo O13.3, O13.4
Brunner, Han O8.3
Bu, Youngmin 70, 134
Buccola, Nancy G. 115
Buch, Helle 39
Bucholz, Kathleen S16.1, S16.3
Buitelaar, Jan O4.2, 2, 3, 7, 9, 11
Bukszar, Jozsef O2.6, 42
Bundo, Miki O1.4, 94
Bunge, Silvia A. ECI 4
Bunney, William E. O7.3
Buonocore, Federica 72, 253
Burdick, Katherine S9.2, O8.6, 167
Burmeister, Margit S6.4, 128, 129
Burton, Cynthia 242
Busatto, Geraldo 104, 113
Butler, Amy W S1.1, O1.3, O7.4,
O11.1, 143
Buttenschøn, Henriette O1.1, O 8.1, 39
N.
Buttigieg, Neil O4.4, 19
Buxbaum, Joseph O12.5, O13.1
Buzas,, Beata 167
Byerley, William F. 115, 157
Byrnes, Andrea 25
Caballero, Alejandro 108
Cadenhead, Kristin 207, 249
Cadigan, Jennifer 283
Caesar, Sian O10.3
Cagliani, R. O12.4
Cahn, Wiepke O11.2, 227, 260
265
Cai, Xueya ECI 14
Cairns, Murray S7.2
Calarge, Chadi S11.4
Calati, Raffaella 140
Calhoun, Vince O6.2
Caligiuri, Michael S6.3
Calkins, Monica 249
Camarena, Beatriz 108
Cannon, Ronald O5.2
Capogna, Michael O5.4
Cappi, Carolina ECI 8
Cardenas-Godinez,
Marcela
ECI 5
Cardone, Laura 208
Carless, Melanie S12.4, S12.5, ECI
13, 76
Carmine Belin, 142
Andrea
Carr, Kenneth O1.6
Carroll, Adam S7.2
Carroll, Liam O12.1, 247
Casas, Miguel 7, 8, 9
Caspi, Avshalom O9.7
Cate-Carter, Tasha 171
Cath, Danielle S10.1, S10.2,
S10.3, S10.4,
S10.7
Cavallini, Maria S10.4
Cristina
Celestrin, Kevin O1.6
Cervilla, Jorge 28
Ceulemans, Shana 52, 122
Chambers,
84
Christopher
Chana, Gursharan S6.2, 213
Chandler, Sharon S6.2, 213
Chang, Byung-Eun 70
Chang, Chien Ching 87, 235
Chapagain, Ram Hari 240
Charlesworth, Jac C S12.4
Chavira, Denise S10.6
Chen, Chao S2.3, S2.5, O8.4,
98
Chen, David ECI 19
Chen, Guo-Lin 68
Chen, Haiming 128, 129
Chen, Hsin-I S6.4, 268, 269,
272
Chen, Jen-Yeu O8.4
Chen, LiShiun S16.4, S16.5, ECI
7
Chen, Peining O2.4
Chen, Suephy 67
Chen, Xiangning O3.5, 42, 179
Cheng, Lijun S2.3, S2.5, 98
Cheng, Min-Chih O8.4
Chiesa, Alberto 185
Chillotti, Caterina 162
Cho, Ah Rang 254
Choi, Jung-Eun 151, 195, 196, 200
Choi, Kyung Sook 46
Chorlian, David ECI 18
Chow, Tze Jen ECI 1, 217, 226
Chowdari, Kodavali 243
Christensen, Jane
Hvarregaard
212, 214
Christensen, Kenneth O1.1
V.
Christian, Susan L. ECI 12
Chung, Hedy 199
Chung, Joo Ho 254
Chung, Myeon-Woo 133
Cichon, Sven S14.3, S14.4,
O5.5, O8.2, O9.2,
O11.6, 119, 148,
149, 160, 197
Cloninger, C. Robert S16.3, 115
Cochrane, Lynne 125
COGA S16.1, S16.3,
S16.6, S16.7, ECI
18, 90
COGEND S16.1, S16.3,
S16.7
Coghill, David 4
Cohen, Andrew 62
Cohen, D 245
Cohen, Nadine 199
Cohen-Woods, Sarah S1.1, O1.3, O7.4,
O11.1, 143, 152,
285
Cojocaru, Mariana 34
Cole, James 285
Coleman, Michael 80
Coleman, Vegas ECI 14
Collier, David S5.2, S7.1, S15.1,
O11.5, O15.2, 83,
153, 236
Colombo, Elisa 188
Colombo, Roberto 188
Condie, Alison O5.2
Congiu, Donatella 162
Consortium on
Lithium Genetics
(ConLiGen)
O9.4
Constante, Miguel 83
Contini, Verônica 14
Contreras, Javier 141
Cook, Ed S10.5, 61

Cools, Roshan 2
Cooper, Jon 72
Corbett, Blythe A. ECI 4
Cordeiro, Quirino ECI 8
Corina, Benjet ECI 5
Cormand, Bru O9.6, 3, 5, 7, 8, 9
Cormican, Paul 125
Correia-Pinto, Julien 75
Cortes, M Jose O6.4
Corvin, Aiden S3.1, S9.1, O12.1,
O15.3, 48, 125
Corydon, Thomas J. 214
Coryell, William S11.4, 157
Cosentino, C. 233
Cox, Nancy S10.3
Cozzi, P. O12.4, 233
Craddock, Nicholas S14.5, O1.3, O5.3,
O7.4, O10.3,
O12.1, O12.5,
102, 143, 160,
210, 285
Craig, David S2.3, 157
Craig, Ian W. S1.1, O1.3, O2.5,
O7.4, O11.1,
O15.2, 143, 152,
164, 190
Craig, Thomas 211
Crane, Jacquelyn S10.3
Crepel, An O13.2
Crespo, José M. 40
Crowley, James O12.3, 23, 25, 229
Cubells, Joseph P4.7, 79
Cuccaro, Michael O3.3, O17.2
Cummins, Tarrant 84
Curran, Joanne S12.4, S12.5, ECI
13, 76
Curtis, David O2.1, ECI 17
Czerski, Piotr 190
Czobor, Pál 234
Dackor, Jennifer 25
Dagdan, Elif 168
Dahl, Hans Atli 27
Dáibhis, Aoife 6
Dal Fiume, C. O12.4
Dale, Anders 64
Daly, Mark 262
Dapretto, Mirella 88
Daróczi, Gabriella 50
DasBanerjee, Tania S8.2, S8.3, 18
Davey Smith, G 32, 93, 114
David, Anthony O15.2
Davies, Charlotte O4.4, 19
Davies, Gail 74
Davis, Jeremy S6.3
Dazzan, Paola O15.2, 211
de Geus, Eco S4.5, S8.1, 147
de Haan, Marcel S10.7
de Jong, Pieter 26
de Jonge, Maretha O13.4
de Kloet, E.R. 60
de La Bastide, Melissa 208
de la Marche, Wouter O13.2, 31, 33
de la Portilla, Sonia O6.4
de Leeuw, Charles N. S3.5
de Luca, Vincenzo 191, 244
de Quervain,
Dominique
255, 256
de Rijk, Peter 136
de Ronchi, Diana 44, 140, 185, 186,
188
de Saloma, Andiara 170
de Sonneville, Leo O13.4
de Zutter, Sonia 52
Deary, Ian O5.2, 74, 208
Dechairo, Bryan 15, 17
Deckert, Juergen 30
Dedman, Alexandra O2.1, 156
Degenhardt, Franziska 119, 160
Del Zompo, Maria 162
Deleuran, Thomas O1.1
Del-Favero, Jurgen 52, 122, 136, 237
DeLisi, Lynn E. 135
Deloukas, Panos O17.1
Delucchi, Kevin S10.2, S10.7
Demirkan, Ayse 147
Demontis, Ditte O8.1, 212
Dempster, Emma O9.5, O14.3,
O14.5, 202, 236
Deng, Hong-Wen 204
Deng, Xiaoyan 184
Dennis, J. Michael 115
Denys, Damiaan S10.2, S10.4,
O11.6
DeRijk, R.H. 60
Derks, Eske O11.2, 260, 265
DeRosse, Pamela S9.2, O8.6, 167
Derringer, Jaime S16.2, S16.4,
S16.6, ECI 10
Desrivieres, Sylvane O14.1
Detera-Wadleigh,
Sevilla
S14.4, O2.2
DeVane, Lindsay S11.2
Devlin, Angela 43
Devlin, Bernie 118, 243
Devriendt, Koen O13.2
Di Forti, Marta O15.2, 105
Diaconu, Carmen C. 149
Diaz Lacava, Amalia 120
Dick, Danielle S16.1, S16.3,
S16.4, S16.6,
S16.7, O14.1,
O16.2, O16.3,
117, 279
Dickinson, Dwight O6.3
Dike, Craig S6.3
Dikeos, D 245
Diniz, Breno 73
Diniz, Mateus 170
Ditzen, Claudia S6.1
Djurovic, Srdjan 53, 64
Doan, Bridget S10.5
Dobie, Dorcas 249
Dobyns, William B. ECI 12
Docherty, Sophia O9.5, 77
Doheny, Kimberly S16.1, S16.3,
S16.4
Dombovári, Edit 50
Domschke, Katharina S1.4, 30
Donohoe, Gary S3.1, S9.1
Doody, Gillian 211
Dorst, Marieke 31
Doud, Mary Kathryn S15.5
Doudney, Kit 184
Downing,
AnnCatherine
O2.4
Downs, B. William 182
Drago, Antonio 44, 186
Dreolini, Lisa S3.5
Drews, Eva 120
Drgon, Tomas 183, 273
Druid, Henrik 230
Duan, Jubao 115, 245
Ducci, Francesca O16.1, ECI 2, 105
Dudbridge, F 245
Duggirala,
Ravindranath
S12.4, S12.5, ECI
13, 76
Duncan, Laramie 103
Dutt, Anirban 83, 236
Dwyer, Sarah O12.1, 210
Dyer, Thomas D. S12.4, S12.5, ECI
13, 76
Ebstein, Richard 11, 91
Edenberg, Howard S16.1, S16.2,
S16.3, S16.4,
S16.6, S16.7, ECI
14, ECI 18, 90,
138, 157
Edman, Gunnar O10.1, O10.5
Egan, Michael O6.3
Eggermann, Thomas 86
Ehlers, Cindy 275
Ehringer, Marissa 69
Eissa, Ahmed 243
Ekwall, Karl 92
Elassy, Mai 243
Elbert, Adrienne 171
El-Boraie, Hala 243
Eley, Thalia C. 144
Elfving, Betina 214
Elkin, Amanda O1.3, 190
Ellingrod, Vicki S11.1, S11.4
Elliott, Paul ECI 2
Elliston, Lynne 247
Elston, Robert C. 148
ENGAGE Handedness 114
Consortium, The
Engert, James O10.2
Erhardt, Angelika O3.2, 30
Eriksson, Elias 30
Erpe, Mariano ECI 14
Escaramís, Geòrgia 40
Eskin, Eleazar 157
Esko, T. 114
Esposito-Smythers,
Christianne
62
Estivill, Xavier 8, 40
Eubank, James O14.3
Evans, DM 114
Evans, Emma O4.4, 19
Evans, Kathy 208
Evdokimova, Oksana 280
Everall, Ian S6.2, S7.3, 213
Evgrafov, Oleg 239
Fagerness, Jes S10.3, S10.4,
S10.5, 61
Fallin, MD 245
Fallon, James 63, 238
Fann, Cathy S-J 87, 205, 235
Fanous, Ayman 42, 179, 223, 261

Faraone, Stephen S6.3, S8.1, S8.2,
S8.3, 3, 9, 11, 15,
17, 18, 118
Farmer, Anne E. S1.1, O1.3, O2.5,
O5.3, O7.4,
O11.1, O11.5,
102, 143, 164,
190, 285
Fasmer, Ole Bernt S14.2, 9
Fathi, Warda 243
Favis, Reyna 199
Fearon, Paul 211
Feier, Gustavo 75
Feiler, Heidi 275
Feinberg, Andrew P3.1, S2.2
Feng, Guoping O3.3, O6.6
Feng, GuoYin O3.3, 38
Feng, Ningping O6.3
Feng, Yu O14.3, 50, 95, 171
Fennell, Alanna 173
Fernandez, Cathy O13.3
Fernandez, Guillen O8.3
Ferraro, Thomas N. 41
Ferraz Alves, Tania 113
Ferrier, Nicol O5.3, O10.3
Filges, Isabel 256
Filiou, Michaela S6.1
Fisher, Helen O15.2, 211
Fisher, Sherri S16.3
Flint, Jonathan O3.5
Flint, Tracey J O1.1, O8.1
Flodman, Pamela O5.1
Flores, Deborah 141
Foldager, Leslie O1.1
Forero, Diego 52, 122
Forlenza, Orestes 73
Foroud, Tatiana S16.6, ECI 14,
ECI 18, 90, 157
Forsell, Yvonne O1.2, O7.3, O9.1
Forstner, Andreas J. O8.2, O9.2
Fox, Helen 74
Fox, Louis S16.3, S16.5
Fox, Peter T S12.4
Frangou, Sophia 153
Frank, Christopher L. S15.5
Frank, Josef 197
Franke, Barbara O4.2, O8.3, O9.6,
2,3,5,7, 9, 11
Franke, Thomas O1.6
Franti, Lindsay 89
Fraser, Christine O10.3
Freedman, Robert 115, 249
Freeman, Natalie 202
Freimer, Nelson S10.3, ECI 2
Freitag, Christine O4.1
Freudenberg, Jan O9.2
Frisen, Louise O10.1, O10.5
Fryland, Tue 214
Fryns, Jean-Pierre O13.2
Fu, Cynthia 285
Fu, Dong-Jing 199
Fuchs, Karoline 152
Fujii, Takashi 66
Fukuhara, Chiaki 67
Fukunaka, Yuko 268, 269, 272
Fumagalli, M. O12.4
Furney, Simon O17.4
Gaafar, Hanan 243
Gádoros, Julia 50
Gage, Fred P1.1
Galea, Sandro 110
Gallagher, Louise O15.3, 258
Galter, Dagmar 142
Ganda, Clarissa 57
Gao, Cheng-Ge 204
Gardiner, Erin S7.2
Gargus, Jay O5.1
Garrido, Helena S10.6
Garriock, Holly S1.2
Gastaminza, Xavier 8
Gates, Amy 125
Gattaz, Wagner 73, 75, 198
Gaudi, Simona 238
Gaysina, Dasha 285
Ge, Dongliang O11.3, 254
Ge, Xuecai S15.5
Gejman, Pablo V. 115, 245
Gelernter, Joel 110
GENEVA S10.3, S16.1,
S16.2, S16.3,
S16.6, S16.7
Genro, Julia 13
George, Charles J. 202
Georgieva, Lyudmila O12.1, O12.5
Gerrish, Amy O17.1, 247
Gershon, Elliot S2.3, S2.5, S5.3,
127, 157, 180
Geschwind, Daniel 94
Geyer, Mark S6.3, 146, 207
Ghadiri, Mohammad 97, 158
Giacometti, Emanuela S3.6
Gibbs, Anne 80
Gibbs, Richard O12.3
Giegling, Ina O12.1, 186
Gilbert, Donald L. ECI 4
Gilder, David 275
Gilks, Will 125
Gill, Michael S3.1, S9.1, O12.1,
O17.1, 4, 6, 10,
11, 12, 16, 21, 48,
125, 143, 258
Gillespie, Charles 79
Giltay, E.J. 60
Girardi, Paolo 153
Gizer, Ian 275
Gladwin, Thomas 260, 265
Glahn, David S12.4, S12.5, ECI
13, 76
Glaser, B 32, 93
Glatt, Stephen S6.2, 82, 213
Glessner, J 32
Goate, Alison S16.3, S16.5,
O17.1, ECI 7
Goenjian, Armen 65
Goes, Fernando 150
Gogos, Joseph A. S3.4
Golding, J 32
Goldman, David O1.7, O16.1, 167
Goldman, Lynn R O16.1
Goldstein, David O11.3, 254
Golimbet, Vera 280
Gomez, Lissette O14.3, 171
Gómez-Barros, Nuria 8
Gomez-Sanchez,
Ariadna
ECI 5
Gonzalez, Laura 108
Goodman, Marianne O1.7
Goossens, Dirk 122, 136, 237
Gordon-Smith,
Katherine
O10.3
Göring, Harald S12.4, S12.5, ECI
13, 76
Gow, Alan 74
Graae, Lisette 142
Grant, SFA 32
Gratacòs, Mònica 40
Gray, Joanna 285
Green, Elaine O5.3, O10.3
Green, Michael 249
Greenwood, Tiffany S9.4, S14.2, O7.6,
157, 166, 180,
207, 249, 283
Gregersen, Noomi 27
Grevet, Eugênio H. 14
Grigoroiu-Serbanescu,
Maria
148, 149
Groß-Lesch, Silke 8
Grove, Tyler S11.1
Grozeva, Detelina O5.3, O10.3, 19
Grucza, Richard S16.2, S16.3,
S16.4, S16.5,
S16.6, ECI 7
Gruenewald, Ellen 51
Gschwind, Leo 255, 256
Guerrini, Irene ECI 17
Guffanti, Guia O6.2, 63, 132,
238, 264
Guidry, Jami 242
Guijarro-Domingo,
Silvina
8
Guilherme, Luiza ECI 8
Guillozet-Bongaarts,
Angela
232
Guindallini, Camilla 170
Guitiérrez-Zotes,
Alfonso
40
Gunasinghe, Cerisse 285
Guo, An-Yuan O3.5, 266, 267
Guo, Ting-Wei 204
Gupta, Ajay O2.2
Gur, Raquel 76, 249
Gurling, Hugh O2.1, ECI 17, 59,
156
Gutiérrez, Blanca 28
Gwilliam, Rhian O17.1
Haas, Magali 199
Haavik, Jan S14.2, O9.6, 3, 5,
7, 8, 9
Hack, Laura O16.2
Haggarty, Stephen S15.5
Hagoort, Peter O8.3
Haines, Jonathan O17.2
Hakonaron, Hakon S13.1, S13.2, 32
Hall, Mei Hua S12.3, 80, 240
Hall, Stephanie 15, 17
Halmoy, Anne S14.2, 7
Hamdan, Adnan 206
Hamilton, Steven S1.2, ECI 6
Hamshere, Marian O10.3, O12.1,
O17.1, 160

Han, Baoguang O2.4
Han, Yan 204
Hanna, Gregory S10.4, S10.5, 61
Hansen, Aase 39
Hansen, M. O1.1, 245
Hansen, Thomas 212
Haraksingh, Rajini 130
Hardin, Jill O16.4
Hare, Elizabeth 141
Harold, Denise O17.1
Haroutunian, Vahram O12.5
Harris, Adam S13.5
Harris, Sarah 74, 208
Hartikainen, Anna-
Liisa
ECI 2
Hartmann, Annette O12.1, 186
Hartz, Sarah 138
Hashimoto, Eri 94
Hashimoto, Hitoshi O6.5
Hashimoto, Ryota 66, 215
Hatsukami, Dorothy S16.5, ECI 7
Hattori, Kotaro 66
Hauser, Joanna S1.1, O2.5, 190
Hawi, Ziarah 4, 10, 12, 21
Hawkin, William O5.2
He, Guang O6.1, 38
He, Lin O6.1, O7.1, 38
Head, Jennifer 283
Heath, Simon O1.3, O7.4, O11.1
Heck, J. Denis O5.1
Hedemand, Anne O8.1, 27, 212
Heine, Monika 9
Heinz, Andreas 197
Henigsberg, Neven S1.1, O2.5, 190
Hennah, William S15.2, 189, 208
Hennings, Johannes S1.4
M.
Her, Charles-Henry 156
Heresco-Levy, Uriel 91
Heriani, H 57
Herms, Stefan 119, 149
Hernández, Sandra 108
Heron, Eleisa 258
Heron, Jon O4.3
Hervás, Amaya 8
Hesselbrock, Victor S16.1, S16.2,
S16.3, S16.6,
S16.7
Hessl, David 22
Hester, Robert 84
Hettema, John O3.5
Heutink, Peter S4.1, S4.5
Heyrman, L 237
Higuchi, Teruhiko 66
Higuchi, Ttsuro 121
Hill, Francesca 72
Hill, Matthew 21, 48, 168, 253
Hinds, David O16.4
Hinrichs, Anthony S16.3, S16.5
Hipolito, Maria O11.4, 157
Hippman, Catriona 107
Hirata, Yuko 172
Hoda, Farzana 285
Hodge, Susan ECI 6
Hodges, Angela O17.4
Hodgkinson, Colin A O1.7, O16.1, 167
Hof, Patrick O13.1
Hoffmann, Per 174
Hofman, Albert O7.2
Hoft, Nicole 69
Hohmann, John 232
Hokyo, Akira 82
Hollander, Jonathan S7.4
Hollingworth, Paul O17.1
Holmans, Peter O5.3, O10.3,
O12.1, O12.5,
O17.1, 245
Holsboer, Florian S1.4, O3.2, O15.1,
100, 101
Holst, Martin O12.2
Holt, Robert A. S3.5
Honda, Hiroyuku 215
Honer, William 107
Hoogendijk, Witte S4.1, S4.5
Hoogman, Martine 2
Hoop, Jinger P2.3
Horan, Michael 74
Hori, Hiroaki 66
Horstmann, Sonja S1.4
Hosang, Georgina 102
Hottenga, Jouke-Jan 114, 147
Hou, Wei-Kun 204
Hougaard, David
Michael
O8.1
Hounie, Ana S10.4, S10.5, ECI
8, 61
Houser, Melissa 259
Hovatta, Iiris O3.4
Howells, William S16.1, S16.3
Howrigan, Daniel 118
Hsu, Pei-Chun 87, 205, 235
Hu, Xiaolan 15
Hua Hall, Mei 83
Huang, Ke O6.1
Huber, Andreas 255
Hudziak, James S8.1
Huezo-Diaz, Patricia
Hukic, Diana
190
Hulse, Gary 192
Hulshoff Pol, Hilleke
E.
85, 227
Hultman, Christina 224, 225
Hunt, Stephen 59
Hunter, Jason R. 71
Hunter, Mary-Jill 107
Hussain, Hamid 139
Hutchison, Kent 69
Hutz, Mara 13
Hwang, Rudi S11.5
Hwu, Hai-Gwo 87, 205, 228, 235
Hyde, Thomas 232
Iacono, William G. ECI 10
Iaenisch, Rudolf S3.6
Ibrahim, Ibtihal 243
Ibrahim, Nahed 243
Ichiba, Mio 121, 123
Ickovicz, Abel 171
Iijima, Yoshimi 66
Iizuka, Yukihiko O6.3
Ikeda, Masashi 215
Ikram, MA 114
Ilott, Nicholas 24
Im, Heh-In S7.4
Inada, Toshiya 176, 220, 222, 274
Ingason, Andres S5.2
Inoue, Ken 29
International Group
for The Study of
Lithium Treated
Patients, IGSLI
O9.4
Interheart
Investigators
O10.2
Ioannidis, John 30
Irizarry, Rafael S2.2
Irmansyah, I 57
Irons, Daniel E. ECI 10
Ishigooka, Jun O1.4
Ishihara, Ryoko 231
Ising, Marcus S1.4, O3.2, O15.1,
100, 101
Israel, Salomon 91
Ito, Yoshihito 176, 209, 220,
221, 222, 231
Iuvone, Michael 67
Ivanov, Dobril O5.3
Iwamoto, Kazuya S2.1, O1.4, 94
Iwata, Nakao 215, 220, 221,
222, 274
Iyegbe, Conrad 105
Iyo, Masaomi 274
Izzo, Giselle 73
Jablensky, Assen S3.1
Jack, Lisa O16.4
Jackson, Sarah 106
Jacob, Christian P. O4.1, O9.6, 5, 7,
8, 9
Jacobsen, Kaya S14.2, 7
Jancic, Dunya S14.3
Janiri, Luigi 188
Jansen, Andreas 86
Janssens, Cecile 147
Järvelin, Marjo-Riitta ECI 2
Jay, M 245
Jayathilake, Karu O6.5
Jazin, Elena 251
Jenkins, Gregory S1.2
Jerez, Alvaro 141
Jerman, Borut S1.1, O2.5
Jia, Peiin O2.6, 42, 266, 267
Jiang, Lin 251
Jin, Choon-Jo 151
Joensen, Sofus 27
Johansson, Stefan S14.2, 3, 7, 8, 9
Johnson, Catherine 183, 273
Johnson, Eric S16.3, S16.4,
S16.5, ECI 7
Johnson, Katherine 6
Johnson, Matthew P. S12.4
Johnson, Paul 45
Jonathan, Sebat S5.4
Jones, Allan 232
Jones, Ian O5.3, O7.4,
O10.3, 102
Jones, Lisa O5.3, O7.4,
O10.3, 102, 285
Jones, Peter 211
Joo, Eun-Jeong 46, 47
Joyce, Peter 184
Joyner, Alexander 64

Judy, Jennifer S14.1, 154, 257,
263
Jugurnauth, Sarah S7.1
Jurkeniene, Lina 109
Kaakinen, Marika ECI 2
Kaczvinszk, Emília 50
Kærgaard, Anette 39
Kærlev, Linda 39
Kahn, Rene O11.2, 81, 85,
227, 234, 260, 265
Kaiya, Hisanobu ECI 11, 29
Kakiuchi, Chihiro 37, 177
Kaladjieva, Luba S3.1
Kalita, J 78
Kallunki, Pekka O1.1
Kalsi, Gursharan O16.2
Kamail, Masoud 89, 161
Kamar, Sher Bahadur 240
Kan, Cees 2, 7, 9
Kananen, Laura O3.4
Kanazawa, Tetsufumi 82, 193
Kand, Tae Sun 133
Kandaswamy, ECI 17, 156
Radhika
Kandil, Karim 243
Kane, John S9.3
Kaneva, Radka 277
Kang, Seung-Gul 195, 196, 200
Kang, Sung Wook 254
Kang, Xin 239
Kano, Yukiko 35, 37
Kanyas, K. O12.4
Kaplan, Allan S 20
Kapoor, Manav 111
Kapornai, Krisztina 50, 202
Kaprio, Jakko O14.1
Kapur, Suman 111, 112
Karayan, Ida 65
Karlsson, Robert 142
Kas, Martien O13.3, O13.4
Kasai, Kiyoto 37
Kasper, Siegfried 140
Katerberg, Hilga S10.2
Kato, Maiko 121
Kato, Nobumasa 35
Kato, Tadafumi S2.1, O1.4, 94
Kaufman, Liana ECI 15
Kawamura, Yoshiya 29, 35, 37, 177
Kawashige, Seiya 82, 193
Kaye, Walter S13.2, S13.3,
S13.5
Ke, Xiayi 74
Keavney, Bernard O10.2
Keefe, Richard S. E. 229
Keers, Robert 102, 190
Keller, Matthew 103, 246
Kelly, Brian 68
Kelsoe, John P4.5, S9.4, S14.2,
O7.3, O7.5, O7.6,
56, 146, 157, 166,
169, 180, 201,
242, 283
Kember, Rachel 294
Kemner, Chantal 81
Kendler, Kenneth S16.7, O3.5,
O16.2, O16.3, ECI
3, 42, 115, 179,
223, 245, 261, 279
Kennedy, James S10.5, S11.5, 20,
30, 50, 61, 172,
178, 191, 202
Kennedy, Martin 184
Kennemer, Michael O16.4
Kenny, Elaine 125
Kenny, Paul S7.4
Kent, Lindsey 4, 10
Kerem, Zekeria 139
Kerner, Mallory 182
Kerr, Elizabeth 171
Kertes, Darlene A. 279
Khemka, Deepak 137
Kiefer, Falk 197
Kiemeney, Lambertus 7
Kikuyama, Hiroki 82, 193
Kilpatrick, Dean 110
Kim, Hak Jae 254
Kim, Hyun Sook 46
Kim, Jeong-Hyun 70, 134
Kim, Jong Woo 254
Kim, Leen 195, 196
Kim, Se Hyun 47
Kim, Su Kang 254
Kim, Yong Sik 47
King, Mary-Claire S5.1
King, Nicole 172
Kinnell, Hazel 51
Kinon, Bruce O2.4
Kinoshita, Yoko 215
Kircher, Thilo 86
Kirley, Aiveen 4, 10
Kirov, George S5.2, O5.3, O10.3,
O12.1, O12.5, 19,
247
Kirschbaum, Clemens O7.2
Kiss, Eniko 50, 202
Klei, Lambertus 243
Kleinman, Joel 232
Klimecki, Walt 56
Kloiber, Stefan S1.4, O3.2, 100
Klok, M.D. 60
Knappskog, Per 7, 8, 9
Knight, Helen O5.2
Knowles, James S10.4, 239
Ko, Seong-Gyu 70, 134
Kochunov, Peter S12.4
Kockum, Ingrid 142
Kodama, Masafumi 274
Koehler, Angela N. S15.5
Koenen, Karestan 110
Koenigsberg, Harold O1.7
Koga, Minori 215
Koh, Jun 82, 193
Kohli, Martin A. S1.4
Koide, Takayoshi 220
Koishi, Shinko 35
Kojima, Toshio O1.4
Kolachana, Bhaskar O6.3
Koller, Daniel O10.4, ECI 14,
157
Kolstad, Henrik 39
Komel, Radovan 49
Konishi, Yoshiaki ECI 11
Konneker, Thomas 25, 229
Kooij, J.J. Sandra 7, 9
Korbel, Jan O. 130
Korszun, Ania O1.3, O7.4, 102,
143
Koszycki, Diana 178
Kothencné, Viola
Osváth
50
Kovacic, Zrnka 190
Kovacs, Maria 50, 202
Kovas, Yulia 77
Kozel, Dejan 190
Kracht, Sören 86
Kraft, Jeffrey S1.2
Kramer, John S16.1, S16.2,
S16.3, S16.4,
S16.6, S16.7
Krasteva, Dorita 277
Krastoshevsky, Olga 80
Krause, Verena 80
Kreiker, Susanne 7, 8
Kremen, William S6.2, 213
Kremensky, Ivo 277
Krieger, Jose Eduardo 276, 278
Kripke, Daniel O7.5, 56, 201
Kristensen, Ann Suhl 30, 39
Kronholm, Erkki O1.5
Krueger, Robert S16.1, S16.2,
S16.3, S16.4,
S16.6, S16.7, ECI
10
Krug, Axel 86
Kruggel, Frithjof 63, 132
Kruse, Torben 27
Kuan, Leonard 232
Kukita, Camila 73
Kumar, Ravinesh A. ECI 12
Kumari, Meena O7.2
Kuntsi, Jonna 11
Kunugi, Hiroshi 66
Kuo, Po-Hsiu O3.5, O16.2
Kuperman, Samuel S16.1, S16.2,
S16.3, S16.6,
S16.7
Kurian, Sunil S6.3
Kusenda, Mary O13.5
Kushima, Itaru 174, 209, 220,
221, 222
Kusumawardhani,
Agung
57
Kusumi, Ichiro O1.4
Kyra, Kanyas 206
Labad, Antonio 248
Lachman, Herb O5.4
Laenerts, A-S 237
Lahiri, Debomoy S6.3
Lahti, Jari 189
Lai, I-Ching O8.4
Laird, Nan 118
Lakatos, Anita 63, 132
Lambert, Christophe O17.3
Lancet, D. O12.4
Landaas, Elisabeth 7
Landen, Mikael O10.1, O10.5
Landgraf, Rainer S6.1
Langenecker, Scott 89, 161
Langley, Kate O4.3, O4.4, 1, 19
Laranjeira, Ronaldo 276, 278
Larsen, Eric 190

Lasseter, VK 245
Lathrop, Mark O1.3, O7.4,
O11.1, 164
Laurent, C. 245
Laurie, Cathy S16.1
Lavebratt, Catharina O1.2, O7.3, O9.1,
92
Law, Matthew 203
Lawlor, Brian O17.1
Lawrence, Jacob O2.1, ECI 17, 59,
156
Lawson, William O11.4, 157
Lazzeroni, Laura 249
Lea, Vella 242
Lecrubier, Yves 140
Lee, Hee Jae 254
Lee, Heon-Jeong 151, 195, 196, 200
Lee, James 275
Lee, Kyu Young 46, 47
Lee, Migyung 250
Lee, Richard 99
Lee, Sang Kil 67
Lee, Sun-Young
Lee, Yohan
151
Leff, Julian 211
Leibenluft, Ellen 163, 165
Lekman, Magnus 142
Lemenager, Tagrid 197
Lenaerts, An-Sofie 122
Lencz, Todd S9.2, S9.3, O8.6
Le-Niculescu, Helen S6.3, O10.4
Lennartsson, Andreas 92
Lepard, Tiffany 106
Leppä, Virpi O1.5
Lerer, Bernard O12.4, 233, 238,
245
Lesch, Klaus-Peter O4.1, O9.6, 3, 5,
7, 8, 9
Levin, Raz 91
Levinson, Douglas F. 115, 245
Levitan, Robert D 20
Levy, Deborah 80
Lewis, Cathryn M S1.1, O1.3, O2.5,
O7.4, O11.1, 143,
153, 164, 170
Lezheiko, Tatyana 280
Li, Chao O6.3
Li, Dawei ECI 16
Li, Qingqin 199
Li, Rick 115
Li, Tao O6.1
Li, Wenbiao 79
Liang, KY 245
Liao, Ding-Lieh O8.4
Liao, Isaac ECI 4
Libiger, Ondrej S13.5
Lichtenstein, Paul 224, 225
Lieb, Roselind O15.1, 100, 101
Lieberman, Jeffrey A. S11.5, O2.6,
O12.3, 191, 229
Liedel, Stephanie O9.6, 5
Lienard, Patricia 140
Liewald, David 74
Light, Gregory 207, 249
Lin, Michelle O4.1
Lin, Peng 138
Lindefors, Nils O3.1
Lindgren, CM 114
Lindholm Carlstrom,
Eva
251
Linotte, Sylvie 140
Linse Peterson, Greta O17.3
Lionel, Anath 158
Liou, Ying-Jay O8.4
Lit, Lisa ECI 4, 22
Liu, Chih-Min 87, 205, 228, 235
Liu, Chunyu S2.3, S2.5, S5.3,
127, 157, 180
Liu, Qing Rong 183
Liu, Tze-Tze 205
Liu, Wenlei O2.4
Liu, Xiao-Gang 204
Liu, Xiaoxi 35, 37, 177
Liu, Xinmin 163
Liu, Youfang 224, 225
Liu, Yue 204
Liu, Yu-Li 87, 205, 228, 235
Livingston, Gill O17.1
Lloyd, K.C. Kent 26
Lochner, Christine S10.2, S10.4
Logan, Richard O14.3
Loh, Han Chern ECI 1, 217, 226
Lohoff, Falk W. 41, 157
Lohr, James S6.3, 213
Lönnqvist, Jouko O3.4, 189
Lonsdorf, Tina O3.1
Loo, Sandra 15, 17
Lorentzen, Steinar 53
Loukola, Anu O1.5
Lourdusamy,
Anbarasu
O14.1, 281
Lovestone, Simon S15.1, O17.1,
O17.4
Lovett, Maureen 171
Low, Nancy C. O9.3
Lu, Q. Richard S15.4
Lu, She-Min 204
Lucae, Susanne S1.4, 100
Luciano, Michelle 74
Ludwig, Kerstin 174
Luis, Rohde 13
Lunnon, Katie O17.4
Luo, Wei 98
Lupoli, Sara O12.4, 63, 233
Luzi, Sonija O15.2, 105
Lydall, Gregory J. ECI 17, 59
Lynskey, Michael S16.2, S16.3,
S16.4, 277
Lysaker, Paul S6.3
Ma, Jie 204
Maccarrone,
Giuseppina
S6.1
Macciardi, Fabio O6.2, O12.4, 233,
63, 132, 238, 264
Macintosh, Andrew S3.2
Macintyre, Donald O5.2
Maclean, Alan O5.2
Maddox, Connie 67
Madison, Jon S15.5
Magi, R. 114
Magistretti, Pierre S13.2, S13.5
Maher, Brion O3.5, ECI 3, 223,
261
Mahon, Pamela 257
Maia, Jessica O11.3, 254
Maier, Wolfgang S1.1, S14.4, O2.5,
O17.1, 143, 190,
245
Makarov, Vladimir 165
Malaspina, Dolores 239
Malhotra, Anil S9.2, S9.3, O8.6,
ECI 9, 165
Malhotra, Dheeraj 165
Malki, Karim O2.5
Mallet, J. 245
Malloy, Mary O5.2, 216, 237
Malone, Molly 171
Manchia, Mirko O9.4, 162
Mandelli, Laura 185, 188
Mangino, M. 114
Manji, Husseini 199
Mann, Karl 197
Manor, Iris 11
Mansour, Hader 243
Mantripragada, Kiran O4.4, 19
Manz, Niklas ECI 18, 90
Mao, Yingwei S15.5
Marco, Di Nicola 188
Margolis, Russell L. 135
Mari, Jair 170
Markov, Valentin 86
Marks, Michael 59
Maron, Eduard 30
Marques, Andrea ECI 8
Marshall, Nicolette 236
Martin, Andrew O4.4, 19
Martin, Nick S12.1, 114
Martinez Levy,
Gabriela Ariadna
ECI 5
Martinotti, Giovanni 188
Martorell, Lourdes 40, 248
Marusic, Andrej 190
Massat, Isabelle 140
Mathé, Aleksander 92
Mathews, Carol S10.1, S10.2,
S10.3, S10.4,
S10.5, S10.6,
S10.7, 61
Mathur, Aditi 203
Mattheisen, Manuel 119, 160
Mattingley, Jason 84
Mattingsdal, Morten 53
Mavroconstanti,
Thegna
7
May, Todd 213
Mayer, László 50
Mazza, Marianna 188
McCarthy, Mark ECI 2, 114
McCarthy, Michael 201
McCarthy, Shane 165, 291
McClay, Joseph L. O2.6
McClellan, Jon S5.1
McClure, Jennifer O16.4
McCombie, W.
Richard
208
McCracken, Jim 17
McDonald, Colm 236
McEvoy, Joseph O11.3, 254
McGeary, John E. 58, 62
McGhee, Kevin O5.2, 74
McGrath, Patrick S1.2

McGuffin, Peter S1.1, O1.3. O5.3,
O7.4, O10.3,
O11.1, O11.5,
O15.2, 102, 143,
152, 164, 190, 211
McHugh, Patrick 184
McInnis, Melvin S6.4, 89, 128, 129,
157, 161
McKeigue, Paul 170
McKeon, Patrick 168
McKinney, Rebecca O7.5, 166, 201,
283
McLeod, Howard 23
McMahon, Francis S14.3, S14.4,
O2.2, 5.5, O11.6,
ECI 19, 30, 127,
157, 163, 165
McNealy, Kristin 88
McNeill, Geraldine 74
McQueen, Matthew 118, 246
McQuillin, Andrew O2.1, ECI 17, 59,
156
McRae, Allan O5.2, 208
Meaburn, Emma O14.5
Medland, SE 114, 116
Megson, Ian 203
Meier, Sandra 160
Meiser, Bettina P2.1
Melas, Philippe 92
Melle, Ingrid 53, 64
Meltzer, Herbert O6.5, 191
Menchón, José
Manuel
40
Mendez, Enrique ECI 5
Mendlewicz, Julien 140, 190
Mendoza, Rickardo 141
Menezes, Paulo 104, 113
Menke, Andreas S1.4
Mercer, Kristie 79
Merikangas, Alison O15.3, O15.4
Metspalu, Andres 30
Meye, Frank O13.3
Meyer, Jerrold O4.1, 68
Meyer, Jobst O4.1
Michelon, Leandro 104, 113
Mick, Eric 3, 9, 15, 17, 155
Middeldorp, Christel 147
Middleton, Frank S8.1, S8.2, S8.3,
18
Miguel, Euripedes ECI 8
Mikhailov, Anna 173
Mikkelsen, Sigurd 39
Milanesi, L. 233
Mill, Jonathan O9.5, O9.7,
O14.1, O14.5, 24
Millar, Kirsty 208
Miller, Del S11.1
Miller, Gregory 68
Minassian, Arpi 146, 242
Minato, Takanobu 29
Mir, Asif ECI 15, 173
Mira, Korner 206
Miralles, Carmen 248
Miranda, Ana 11
Miranda, Eduardo 54, 55
Mishra, U.K. 78
Missaglia, Sara 188
Mitchell, Philip P2.1
Miyagawa, Taku 29
Miyamoto, Jill 69
Moebus, Susanne O8.2, O9.2, 119
Moens, Lotte 52, 122, 136
Moessner, Rainald O3.3
Moffitt, Terrie O9.7
Moghimi, Narges 158
Molina, Esther 28
Moline, Jessica S11.1
Moller, Hans-Jurgen O12.1, 186
Monakhov, Mikhail 91, 280
Monnier, Philippe O14.3
Moon, Randall S15.5
Moreno, Ricardo 198
Morgan, Craig O15.2, 211
Morgan, Kevin O17.1, 211
Morgan, Margaret O12.3
Morgan, Marsha 59
Morken, Gunnar 53
Morris, Brian 45
Morris, Derek S3.1, S9.1, O12.1,
48, 125
Morris, Noella Marie 192
Mors, Ole S1.1, O1.1, O2.5,
O8.1, 27, 30, 39,
143, 190, 212, 214
Mortensen, Preben Bo O8.1
Moses, Eric K. S12.4, ECI 13
Moskvina, Valentina O10.3, O12.1,
O12.5
Mostafavi-
Abdolmaleky, Hamid
O14.4
Motala, Farhana 16
Mouri, Akihiro 215
Mowry, Bryan J. 115, 245
Mueller, Daniel 191
Mueller-Myhsok,
Bertram
S1.4
Muglia, Pierandrea S1.1, O1.3, O7.4,
O11.1, 164
Mühleisen, Thomas S14.4, O8.2, O9.2,
86, 119, 160
Muhonen, Leea 189
Muir, Walter O1.1, O5.2, 208,
216, 237
Mulas, Fernando 11
Müller, Daniel J. S11.5
Müller-Myhsok,
Bertram
S4.2, O3.2, 174
Mulligan, Aisling 6, 16
Muniz, Renan ECI 8
Munsie, Leanne O2.4
Murphy, Dennis S10.4, O11.6
Murray, Robin O15.2, 54, 55, 83,
104, 105, 211, 236
Murray, Sarah S. S13.5
MvGough, Jim 17
Na, Han Sung 133
Nabeshima, Toshitaka 215
Nagai, Taku 209, 231
Nakamura, Jun 215, 268, 269, 272
Nakamura, Masayuki 121, 123, 124
Nakamura, Yukako 176, 209, 220,
221, 222
Nakano, Yoko O1.4, 94
Nalls, Michael O5.5
Nandam, Sanjay 84
Nasrun, Martina 57
Nathan, Pradeep 84
Navon, Ruth 126
Neagu, Ana I. 149
Neale, Benjamin P4.4, S10.3,
S10.4, 15, 17, 114,
116, 262
Neale, MC 116
Need, Anna O11.3, 254
Negrão, André
Brooking
276, 278
Negri, Gloria 188
Nelson, Elliot 138
Nelson, Stanley 15, 17
Nertney, D. 245
Nesheva, Eleonora 277
Nestadt, Gerald S10.4, 245
Neuhoff, Nina 174
Neuman, Rosalind S16.1, S16.3
Neuroimaging
Initiative, Alzheimer’s
Diesease
63
New, Antonia O1.7
Ng, Mandy Y S1.1, O1.3, O7.4,
O11.1, 143
Nguyen, Trang O4.1, O9.6, 5
Ni, Xingqun 191
Nicodemus, Kristin 219
Nicolini, Humberto S10.4, 141
Niculescu, Alexander S6.3, O10.4
Nielsen, Anders Lade 214
Nieratschker, Vanessa O8.2, O9.2, 86,
119
Nievergelt, Caroline O7.5, 56, 157
Nigg, Joel S8.4
Nikamo, Pernilla O10.1, O10.5
Nikolov, Ivan O10.3, O12.1
Nikolov, Momchil 277
Nimgaonkar,
76, 118, 243
Vishwajit
Nisenbaum, Laura O2.4
Nishida, Hisami 37
Nishida, Nao 29
Njau, Reuben O2.4
Nnadi, Charles 167
Noble, Ernest 65, 181
Nocon, Agnes 101
Noda, Yukihiro 209, 231
Noens, Ilse O13.2, 31
Noethen, Markus M. O5.5, 148, 149
Nogueira, Mariana 8
Nohesara, Shabnam 97
Nolen, Willem 147
Nonkens, Lourens O13.3
Noor, Abdul ECI 15, 158, 173
Nordentoft, Merete O1.1, O8.1
Nørgaard-Pedersen,
Bent
O8.1
Nørmølle
Buttenschøn, Henriette
27

Norrback, Karl- 52, 122, 136
Fredrik
Norton, Nadine O12.1, 245
Nothen, Markus S14.3, S14.4,
O8.2, O9.2,
O17.1, 119, 160,
174, 197
Novak, Melinda 68
Nowrouzi, Behdin 172
Nuechterlein, Keith 249
Nugent, Nicole 110
Nurnberger Jr., John S6.3, S16.1,
S16.2, S16.3,
S16.6, S16.7,
O10.4, O11.4, ECI
14, 30, 138, 157
Nwulia, Evaristus O11.4, 157
Nyegaard, Mette O1.1, O8.1, 27,
212, 214
Nymberg, Charlotte O14.1
O’Donovan, Michael 160
Oades, Robert D 11
Oberlander, Tim 43
O'Donoghue, Therese S9.1
O'Donovan, Lucy 45
O'Donovan, Michael S3.1, S5.2, S9.1,
O4.3, O4.4, O5.3,
O10.3, O12.1,
O12.5, O17.1, 19,
210, 215, 245, 247
O'Dushlaine, Colm 131, 159
Oedegaard, Ketil
Joachim
S9.4, S14.2
Oh, S 245
Ohadi, Mina 158
Ohashi, Mitsuki 231
Ohman, Arne O3.1
Ohmori, Osamu 268, 269, 272
Ohnishi, Tetsuo O2.3
Ohno, Kinji 209
Ojha, Saroj Prasad S12.3, 240
Ojopi, Elida 73, 75, 198
Okahisa, Yuko 274
Okamoto, Nagahisa 66
Okazaki, Yuji ECI 11, 29
Okochi, Tomo 215
Oldham, Michael
Olga, Likhodi
94
Olincy, Ann 249
Ollier, William 74
Olsen, Inger Marie L. O1.1
Olsson, Eric 230
Olvera, Rene O9.8, ECI 13, 76
Omori, Mayu 66
Omri, Teltsh 206
O'Neill, A 245
O'Neill, Francis ECI 3, 179, 223
O'Neill, Raymond R. 26
Ono, Yutaka 176
Ontiveros, Alfonso 141
Oostra, Ben 147
Ophoff, Roel O11.2, 81, 227,
260, 265
Oppelaar, Hugo O13.3
Orro, Alessandro O12.4, 63, 233
Osby, Urban O10.1, O10.5, 230
Oscar-Berman, 182
Marlene
Osimo, Emanuele O12.4, 238
Osnat, Karni 206
Ospina, Luz O13.1
Otowa, Takeshi ECI 11, 29, 30, 35,
37, 177
Otte, David-Marian O12.2
O'Tuathaigh, Colm S3.3
Owen, Michael S3.1, S5.2, S9.1,
O1.3, O4.3, O4.4,
O5.3, O7.4,
O10.3, O11.1,
O12.1, O12.5,
O17.1, 1, 19, 102,
143, 210, 215,
245, 247
Ozaki, Norio 176, 209, 215,
220, 221, 222,
231, 274
Ozkaragoz, Tulin 181
Ozomaro, Uzoezi O3.3
Ozturk, Mine 117
Paddock, Silvia 142
Pae, Chi-Un 185
Palácios, Selma ECI 8
Palejev, Dean 130
Palmason, Haukur O4.1
Panariello, Fabio 244
Panganiban, Corrie 157
Papadimitriou, G 245
Papageorgis, Panos O14.4
Papapetrou, Danae O13.1
Papassotiropoulos,
Andreas
255, 256
Pare, Guillaume O10.2
Paredes, Ursula 170
Pariante, Carmine O15.2
Park, Hyung-Seok 151
Park, HyunJoo 133
Park, Jeong-Su 70, 134
Park, Jin Kyung 254
Park, Joanne 4, 10
Park, Sohee S12.3
Park, Sunju 70, 134
Park, Young-Min 195
Parker, Gordon P2.1
Parla, Jennifer 208
Partonen, Timo O1.2, O1.5, O7.3
Paschall, Justin 157
Passmore, Peter O17.1
Pásztor, Péter I. 234
Patel, Darshana 175
Patel, Sagar S6.3, O10.4
Patterson, Diana O16.2
Paul, Torsten 148, 160
Pauls, David S10.1, S10.3,
S10.4, S10.5,
O4.2, 61
Paunio, Tiina S12.2, O1.5, O7.3
Payo-Cano, Jose L O2.5
Payton, Antony 74
Pedersen, Carsten
Bøcker
O8.1
Pedrosa, Erika O5.4
Pedroso, Inti O11.5
Peeters, Hilde O13.2
Peirce, Timothy O12.1
Peltonen, Leena O3.4, ECI 2, 114,
189
Pendleton, Neil 74
Penninx, Brenda S4.1, S4.5, 147
Pereira, Alexandre
Costa
276, 278
Pereira, Ana-Caterina ECI 17
Perez, Jorge 190
Perez-Rodriguez,
Mercedes
O1.7
Pericak-Vance,
Margaret
O3.3, 17.2
Perkins, Diana O. 229
Perlis, Roy S1.5
Perroud, Nader S1.1
Perry, William 146
Peters, Eric S1.2
Petryshen, Tracey S15.5
Pfister, Hildegard O15.1, 100, 101
PGC Schizophrenia
GWAS Collaboration,
P4.3
The
Phenome Group, The
Bipolar Disorder
S14.1
Philibert, Rob 30
Piccardi, Paola 162
Picchioni, Marco 83
Pickard, Ben O5.2, 216, 237
Pickles, Andrew 74
Pidsley, Ruth O9.5
Pirkola, Sami O1.5, O3.4
Pirlo, Katrina O1.3, O7.4,
O11.1, 143
Pirooznia, Mehidi S14.1, 154, 257,
263
Pitch, Ashley 171
Pitts, Steve O16.4
Pjetri, Eneda O13.3
Placentino, Anna S1.1, O2.5, 190
Plomin, Robert O14.5, 77
Pluzhnikov, Anna S10.3
Poelmans, Geert O4.2
Pogue-Geile, Michael 76
Polanczyk, Guilherme 13
Polgár, Patrícia 234
Porjesz, Bernice S16.1, S16.6,
S16.7, ECI 18, 90
Porkka-Heiskanen,
Tarja
O1.5
Porteous, David S15.2, O5.2, 51,
74, 208
Potash, James S2.2, S14.1,
S14.3, 99, 150,
154, 157, 165,
257, 263
Potkin, Steve O6.2, 63, 132,
191, 238, 264
Pouta, Anneli ECI 2
Powell, John 54, 55, 83, 105
Prado, Carolina 198
Prata, Diana 236
Pratt, Amanda 23
Pratt, Judy 45
Pregelj, Peter 49
Preisig, Martin 143
Prescott, Carol O16.2, O16.3, 279

Price Foundation
Collaborative Group,
The
S13.1, S13.4,
S13.5
Priebe, Lutz O9.2, 119
Prince, Martin 170
Priotsi, P S15.1
Propping, Peter O12.2
Prossin, Alan 89, 161
Psychiatric GWAS P4.2, P4.3, P4.4,
Consortium, The P4.5
Pugh, Elizabeth S16.1, S16.3,
S16.4
Pulver, AE 245
Purcell, Shaun S5.5, S10.3,
S10.4, O2.1,
O12.3, ECI 17,
118, 131, 159
Qi, Hongshi 92
Qian, Yudong 127
Qiu, Chuan 204
Quackenbush, Corey 23, 229
Quesenberry, Charles S1.3
Quevedo, João 75
Quinn, Emma S9.1, O12.1, 48
Racz, Ildiko 120
Radant, Allen 249
Ramakers, Geert O13.3
Ramakrishnan, Kamna 208
Ramos-Quiroga, Josep
Antoni
3, 7, 8, 9
Rangarajan, Sumathy O10.2
Rangaswamy,
ECI 18, 90
Madhavi
Rasmussen, Jerod 132
Raventos, Henriette 141
Rebolini, Danea 208
Redman, Margot S2.3
Reif, Andreas O9.6, 3, 5, 7, 8, 9,
30
Reinalda, Megan S1.2
Remington, Gary 191
Remschmidt, Helmut 174
Renner, Tobias O4.1
Ressler, Kerry 79
Réthelyi, János M. 234
Reus, Victor S1.3
Rex, Katharine 56
Ribases, Marta 7, 8, 9
Ribble, R 245
Ribeiro, Sidarta 75
Rice, John S16.1, S16.3,
S16.5, ECI 7, 115,
138, 143, 157
Richmond, Todd 135
Richter, Margaret S10.5
Richter, Anne 197
Richter, Peggy M. S11.5
Rietschel, J. O2.5
Rietschel, Marcella S1.1, S14.3,
S14.4, O5.5, O8.2,
O9.2, O11.6, 30,
86, 119, 143, 148,
160, 190, 197
Rijpkema, Mark O8.3
Rijsdijk, Fruhling 11, 83, 144
Riley, Brien O16.2, ECI 3, 42,
179, 223, 245, 279
Rimol, Lars 64
Ripatti, Samuli O3.4, 114
Ripke, Stephan P4.1, S1.4, O3.2,
262
Ritchie, Terry 65
Ritter, Benjamin P. 71
Rivera, Margarita 28, 143
Rizzu, Patrizia S8.1
Roberts, Rachel O4.4, 19
Robertson, Ian 6
Robinson, Delbert S9.3
Robinson, M. ECI 17
Rochberg, Nanette 138
Roche, Siobhan 168
Roddey, Cooper 64
Roeske, Darina O3.2
Roeyers, Herbert 11
Rogdaki, Maria 92
Roig, Barbara O6.4
Roman, Tatiana 13, 292
Romanos, Marcel O4.1, O9.6, 5
Romer Ek, Inger O10.1, O10.5
Rommelse, Nanda 11
Rose, Emma S9.1
Rose, Jed 183, 273
Rose, Richard O14.1
Rosenfeld, Jill O6.6
Rosengren, Annika O10.2
Ross, Jessica S10.6
Rothenberger, Aribert 11
Röthlisberger, Benno 255
Rouleau, Guy S10.3
Roy, Alec O16.1
Royall, Josh 232
Ruberto, Gaia 153
Rubinsztein, David O17.1
Ruck, Christian O3.1
Rucker, James 164
Rückert, IM 114
Ruderfer, Douglas 131, 159
Rugulies, Reinar 39
Ruiz, Aida 54, 55
Ruiz-Linares, Andres S10.3
Rujescu, Dan S3.1, S5.2, S9.1,
O12.1, 186
Rupprecht, Rainer S1.4
Rush, A. John S1.4
Russell, Elen O10.3
Saarikoski, Sirkku 189
Sabatti, Chiara S10.3
Sabunciyan, Sarven S2.2
Saccone, Nancy S16.1, S16.3,
S16.5, ECI 7
Saccone, Scott S16.3, 138
Saetre, Peter 251
Sagvolden, Terje 18
Sahoo, Trilochan O6.6
Saito, Toshikazu 94
Sakai, Yoshie 177
Sakata, Shinichi 268, 269, 272
Sakurai, Takeshi O12.5, O13.1
Salah, Hala 243
Salgado, Carlos A. I 14
Salisbury, Dean 80
Salomon, Daniel S6.3
Salvi, Erika O12.4, 63, 233
Samaan, Zainab O10.2
Sampaio, Aline ECI 8
Sánchez-Mora,
Cristina
8, 9
Sanders, Alan R. 115, 245
Sano, Akira 121, 123, 124
Santangelo, Susan L. S12.3, 240
Santarelli, Danielle S7.2
Sarah, Murray 157
Sasaki, Tsukasa ECI 11, 29, 30, 35,
37, 177
Saunders, Erika 89
Saus, Ester 40
Savla, Gauri 242
Saykin, Andrew 63
Scazufca, Marcia 104, 113
Schaefer, Catherine S1.3
Schäfer, Helmut O9.6, 5
Schafer, Martin 186
Schalkwyk, Leonard C O2.5, O14.5
Schalling, Martin O1.2, O3.1, O7.3,
O10.1, O10.5, 230
Scharf, Jeremiah S10.1, S10.3
Scheftner, William 157
Schilling, Karl O12.2
Schilling, Paul 207
Schizophrenia
Genomics Ireland
Consortium, The
O8.5
Schlegel, Kristina 156
Schloegelhofer,
Monika
152
Schmouth, Jean-
Francois
S3.5, 290
Schnack, Hugo G. 85
Schofield, Peter P2.1
Scholte, Evert 31
Schork, Andrew 169
Schork, Nicholas S6.3, S13.1,
S13.2, S13.5,
O10.4, 64, 88,
157, 169, 249,
259, 264
Schork, Ryan 259
Schosser, Alexandra O1.3, O11.1, 143,
152
Schreiber, Stefan 119
Schuckit, Marc S16.6, S16.7
Schulze, Katja 83, 236
Schulze, Thomas S14.3, S14.4,
O2.2, O5.5,
O11.6, 30, 148,
157, 160, 165, 190
Schumacher, Johannes 30
Schumann, Gunter P1.2, O14.1, ECI
2, 281
Schwab, Sibylle
Gabriele
57, 192, 245
Scolnick, Ed ECI 17
Scott, Adrian Phillip 192
Scott, Ashley A. S13.5, 88
Scott, Sarah 4
Seaton-Smith,
Kimberly
275
Sebat, Jonathan P3.2, O13.5
Segall, Judith O6.2

Segall, Samantha 275
Segurado, Ricardo 12
Seidman, Larry 249
Seifuddin, Fayaz S14.1, 154, 257,
263
Seitz, Christiane O4.1
Sens-Espel, Roser 140
Sergeant, Joseph 11
Serretti, Alessandro 44, 140, 185, 186,
187
Service, Susan S10.3
Setó, Sonia 248
Severin, Emilia 34
Severino, Giovanni 162
Severinsen, Jacob 212
SGENE Consortium,
The
S15.1
Sha, Li 216
Shaffer, Lisa O6.6
Shah, Abhishek O5.4
Shah, N Jon 86
Shaheen, S-M S10.5
Shaikh, Madiha 83, 236
Shaikh, Sajid 202
Sham, Pak 54, 55
Sharad, Shashwat 112
Sharma, Rajiv S2.4
Sharp, Frank R. ECI 4
Sharp, Sally 59, 156
Shaw, Duncan 203
Shaw, Marian S13.5
Shekhtman, Tatyana 56, 201
Shen, Elaine 232
Shen, Lei O2.4
Shen, Ling S1.3
Shen, Pei-Hong O16.1
Shi, Jianxin 115, 245
Shi, Yongyong O6.1, O7.1, 38
Shianna, Kevin O11.3, 254
Shimada, Takafumi 29, 35, 37, 177
Shimo, Hirochika 121, 123, 124
Shin, Hee Jung 133
Shinkai, Takahiro 268, 269, 271, 272
Shiokawa, Nari 123, 124
Shirazi, Elham 97
Shrestha, Payas 240
Shtir, Corina 15, 17
Shyn, Stanley S1.2
Sibony, David 191
Sidhu, Shrada 111
Siever, Larry O1.7, 249
Sigmund, Jessica
Charlotte
255, 256
Silberberg, Gilad 126
Silverman, Jeremy M. 71, 115, 245, 249
Simmons, Andrew O17.4
Simon, Mariella O5.1
Simonson, Matthew 246
Simpson, Elizabeth M. S3.5
Simpson, George 239
Sims, Rebecca O17.1
Singh, Karun K. S15.5
Singhapakdi, Kanya 67
Singleton, Andrew O5.5
Sinke, Richard 81
Sinkus, Algimantas 109
Sinkute, Gintare 109
Sironi, M. O12.4
Sitnikova, Tatiana S12.3, 240
Sitskoorn, Margriet 81
Sjöholm, Louise O1.2, O7.3, O9.1
Sklar, Pamela O2.1, O12.3, ECI
17, 118, 131, 159,
224, 225
Skup, Martha 163
Slaats-Willemse,
Dorine
2
Slager, Susan S1.2
Slifer, Michael O17.2
Sliwa, Karen O10.2
Smalley, Susan 15, 17
Smith, Erin 157, 169
Smith, Moyra O5.1
Smith, Rebecca O14.5, 190
Smith, Stevens ECI 7
Smolka, Michael 197
Smoller, Jordan P4.7, S14.6, 118
Snyder, Michael 130
Soares, Dinesh O5.2, 208
Soda, Takahiro S15.5
Sonuga-Barke,
Edmund
11
Soon, Siew Choo ECI 1
Sora, Ichiro 274
Sørensen, Karina
Meden
O8.1
Soria, Virginia 40
Soronen, Pia O1.5, O7.3
Souery, Daniel S1.1, O2.5, 140,
190
Spanagel, Rainer 197
Specht, Michael O3.2
Spector, TD 114
Spirito, Anthony 62
Sprock, Joyce 207
Squassina, Alessio 162
Strik Lievers, L. O12.4
St. Clair, David S15.3, O5.2, O5.3,
O6.1, O10.3, 237
Stanford, Clare 59
Starr, John O5.2, 74, 208
State, Matthew S10.3
Steele, CJM S14.4, ECI 19
Steer, C. 32
Stein, Dan S10.2
Steinhausen, Hans-
Christoph
11
Stergiakouli,
Evangelia
1
Stern, Hal 264
Stewart, S. Evelyn S10.1, S10.2,
S10.4, S10.5
Steyaert, Jean O13.2, 31
Stice, Eric 182
Stiedl, Oliver O13.3
Stitzel, Jerry 69
Stöcker, Tony 86
Stojanovic, Mirjana 152
Stokowski, Renee O16.4
Stolerman, Ian 24
Stone, William 249
Straarup, Steen E. O1.1
Straub, Richard O6.3, 219, 252
Strauss, John 28
Strengman, Eric 81, 234
Strohmaier, Jana S14.4, 160
Stroup, T. Scott 229
Sturgess, Jessica E. S11.5
Subedi, Janardan S12.3, 240
Sudi, Jyotsna ECI 12
Sudic, Diana 230
Sugawara, Hiroko O1.4
Sugaya, Nagisa 29
Sugiyama, Toshiro 37
Suhl Kristensen, Ann 27
Sullivan, Patrick P4.2, S4.1, S4.3,
O2.6, O12.3, 23,
25, 147, 224, 225,
229
Sun, Cuie O3.5
Sun, Jingchun 42, 266, 267
Sung, In-Kyung 151
Sur, Mriganka S3.6
Surakka, Ida O3.4
Suvisaari, Jaana O3.4
Svenningsson, Per 92
Swaab, Hanna O13.3, O13.4
Swan, Gary O16.4
Swanson, Beryl 232
Swerdlow, Neal 207, 249
Syed, Sharifah O4.4, 19
Székely, Judit 50
Szeszko, Philip O8.6
Taillefer, Stephanie S10.5
Takaki, Manabu 274
Takeda, Masatoshi 215
Talati, Ardesheer ECI 6
Talib, Leda 73
Tamang, Swarneem 240
Tamás, Zsuzsa 50
Tamashiro, Kellie 99
Tang, Pek Yee ECI 1, 217, 226
Tang, Yilang 79
Tanii, Hisashi ECI 11, 29
Tassa, Carlos S15.5
Tatarelli, Roberto 153
Tatro, Erick S7.3, 213
Tatsumi, Masahiko 66
Tavian, Daniela 188
Taylor, Grantley 80
Taylor, Stephan S11.1
Tee, Shiau Foon ECI 1, 217, 226
Tenesa, Albert 74
Tenore, Christopher O5.4
Teraishi, Toshiya 66
Terwisscha van
Scheltinga, Afke F.
227
Tesli, Martin 145
Tewari, Deepshikha 78
Tewhey, Ryan S. S13.5
Thapar, Anita O4.3, O4.4, 1, 19,
59
Thiagalingam, Sam O14.4
Thiselton, Dawn 179
Thode, Kirstin O9.8
Thomsen, Jane 39

Thomson, Pippa 51, 208
Thrall, Jenny O11.3, 254
Thrush, Carol 106
Tiemeier, Henning O7.2
Tieran, V. 233
Tikhomorov, Anna S10.3
Tischfield, Jay S10.3, S16.1,
S16.2, S16.3,
S16.4, S16.7
Tiwari, Arun K. S11.5
Tobar, Salwa 243
Tobin, Claire 6
Tochigi, Mamoru 29
Todd, Richard 15, 17
Todorov, Alexandre 15, 17, 277
Tokunaga, Katsushi 29, 35
Tomita, Yasuyuki 215
Tomiyasu, Akiyuki 121, 123, 124
Tooney, Paul S7.2
Topol, Eric J. S13.5, 64
Torkamani, Ali S13.5
Torri, Federica O12.4, 132, 233,
Toulopoulou,
Timothea
Tourette GWAS
Consortium
238
83
S8.3
Toye, Caroline 10
Traskman-Bendz, Lil O10.1, O10.5
Treutlein, Jens 86, 197
Troakes, Claire 72
Tropea, Daniela S3.6
Tsai, Li-Huei S15.5
Tsai, Shih-Feng 205
Tsuang, Debby 249
Tsuang, Ming S6.3, 213, 249
Tsutsumi, Atsushi 82, 193
Turck, Chris S6.1, O12.2
Turetsky, Bruce 249
Turner, Jessica O6.2, 63, 132,
238, 264
Turner, Norris 199
Twamley, Elizabeth 146, 242
Twyman, Roy 199
Uchimura, Naohiko 274
Uchiyama, Hirofumi 66
Ueda, Junko O1.4, 94
Uenishi, Hiroyuki 82
Ueno, Shu-ichi 121, 123, 124
Uher, Rudolf S1.1, O1.3, O2.5,
O7.4, O11.1, 102,
143, 190
Uhl, George 183, 273
Uhr, Manfred S1.4, O3.2, O15.1
Ujike, Hiroshi 274
Ukai, Wataru 94
Umekage, Tadashi 29, 37, 177
Unschuld, Paul G. O3.2
Urban, Alexander
Eckehart
130
Urretavizcaya, Mikel 40
Utge, Siddheshwar O1.5
Utsunomiya, Kensuke 268, 269, 272
Vacic, Vladimir O13.5
Vakkalanka, Krishna O6.3, 252
Valero, Joaquín O6.4, 40, 248
Vallada, Homero ECI 8, 104, 113,
276, 278
Vallender, Eric 68
Valvassori, Samira 75
van Baal, G. Caroline
M.
85
van Beck, Margaret O5.2
van Beijesterveldt,
CEM
S8.1
van Berckelaer-Onnes,
Ina
31
van den Oord, Edwin
JCG.
O2.6, O3.5, ECI 3,
23, 42, 223, 229
van der Does, A.J.W. 60
van Duijn, Cornelia O7.2, 114, 147
van Dyck, Richard 147
van Engeland, Herman O13.3, O13.4
van Haren, Neeltje
E.M.
227
van Lith, Hein O13.3
van Rooij, F. 114
van 't Slot, Ruben 81
VandeBerg, John S12.3, 240
Vasquez, Alejandro 11
Vassos, Evangelos 153
Vawter, Marquis S6.5, O7.3, 238
Vederman, Aaron 89, 161
Veijola, Juha ECI 2
Velders, Fleur O7.2
Veltman, Joris O8.3
Verge, Begoña 248
Verhulst, Frank O7.2
Vetró, Ágnes 50, 202
Vetuz, Glen 10
Victor, Marcelo M. 14
Videtic, Alja 49
Vietan, Cassandra 275
Vilella, Elisabet O6.4, 40, 248
Villa, Catalina O5.4
Vincent, John ECI 15, 158, 173
Vine, Anna ECI 17
Visscher, Peter O5.2, 74, 208
Vladimirov, Vladimir
I.
O2.6, 179
Vogler, Christian 255, 256
von Plessen, Kerstin 8
Vorstman, Jacob O13.4
Vukcevic, Damjan O10.3
Waddington, John S3.3
Wade, Rachel 43
Wagner, Joseph 84
Wagner, Michael S10.4, O3.3
Waite, Roger 182
Walitza, Susanne O4.1, O11.6
Wallace, Douglas O5.1
Walsh, Dermot O16.2, ECI 3, 179,
223, 245
Walshe, Muriel 83, 236
Walss-Bass, Consuelo O9.8
Walters, James S3.1, S9.1
Walther, Donna 183
Wand, Gary 99
Wang, Dai 199
Wang, Jen S16.1, S16.5
Wang, Kai S13.1, S13.2, 32
Wang, Ti O6.1
Wang, Wei 204
Wang, Xiaobin O13.1
Wang, Ying-Chieh O8.4
Warburton, Peter E. 135
Warnke, Andreas O9.6, 5, 174
Watchorn, Amy 6
Watson, Annie 243
Watson, James D. 208
Webb, Bradley O3.5, ECI 3, 42,
223
Webhofer, Christian S6.1
Webster, Maree S2.2
Wegener, Gregers 92, 214
Wei, Jun 203
Weinberger, Daniel O6.3, 219, 252
Weiner, Michael 63
Weinstein, Shauna O1.7
Weissflog, Lena O9.6, 5
Weissman, Myrna ECI 6
Weissman, Sherman 130
Wellcome Trust Case
Control Consortium,
WTCCC
O5.3, O10.3
Weller, Andrew E. 41
Wells, Tony T. 58
Wen, Chun-Chiang 87, 205, 228, 235
Wendland, Jens S14.4, O11.6
Werge, Thomas O8.1, 212
Wessel, Jennifer O16.4
Whalley, Lawrence 74
Wheelan, Sarah 150
White, Angela O5.2
Wickramaratne, Priya ECI 6
Widyawati, Ika 57
Wiedemann, Klaus 197
Wienker, Thomas F. 120
Wigg, Karen O14.3, 171
Wilde, Alex P2.4
Wildenauer, Dieter
Bernd
57, 192, 245
Wilhelm, Kay P2.1
Wilhelmsen, Kirk 225, 275
Willcutt, Erik 103
Willemsen, Gonneke S4.5, 147
Williams, Ben O9.7
Williams, Hywel O12.1, 1, 210, 215
Williams, Ian 83, 236
Williams, Julie O17.1
Williams, Nigel O4.4, O12.1, 19,
245, 247
Williams-Blangero,
Sarah
S12.3, 240
Williamson, Douglas O9.8
Wilson, Nathan S3.6
Winchester, Catherine 45
Winkler, Anderson S12.4
Witasp, Anna 92
Witt, Stephanie 119, 197
Wittchen, Hans-Ulrich 100
Wodarz, Norbert 197
Woldbye, David 27, 30
Wong, Chloe O9.5, O9.7
Wood, Alexis 11

Wood, Joel 243
Wormley, B 245
Woudstra, Saskia S4.1
Wray, Naomi S16.2, 147
Wright, Fred A. 25
Wrobel, Bozena 239
Wu, Joseph O7.3
Wu, Xiaodong 199
Xia, Xuhua 178
Xie, Changchun O10.2
Xu, Xiaohui 170
Xuei, Xiaoling ECI 14
Yamada, Kenji 268, 269, 272
Yamada, Kiyofumi 231
Yamada, Mitsuhiko 274
Yamada, Shinnosuke 209, 231
Yamamoto, Maki 58
Yamamoto, Noriko 66
Yamanouchi, Yoshio 215
Yan, Han 204
Yan, Jia S16.7
Yang, Ueng-Cheng 87, 205, 235
Yang, Wei-Chih 205
Yang, Xiaoju 99
Yankova, Elena 277
Yaqubi, Sahab O14.4
Yassin, Amal 243
Yasui-Furukori, Norio 176
Yehyawi, Nabeel S6.3
Yilmaz, Öznur O12.2
Yilmaz, Zeynep 20
Yim, Seon-Jin 250
Yoav, Kohn 206
Yokoyama, Jennifer S1.2
Yolken, Robert S2.2
Yoneda, Hiroshi 82, 193
Yoon, Seungtai O13.5
Yoshikawa, Takeo O2.3
Yoshimi, Akira 209, 231
Yoshimura, Reiji 215
Young, Allan O5.3, O10.3
Young, James O12.5
Younkin, Steven O17.1
Yu, Dongmei S10.3, 240
Yu, Lan 135
Yuan, Nicole P O16.1
Yuan, Qiaoping O1.7, O16.1
Yusuf, Salim O10.2
Zaharieva, Irina O4.4, 19
Zai, Clement C. S11.5, 191, 244
Zaitlen, Noah 157
Zammit, Stanley O12.1
Zandi, Peter S14.1, S14.3,
O11.4, 154, 157,
257, 263
Zavos, Helena M.S. 144
Zeng, Hongkui 232
Zeng, Zhen O6.1
Zeni, Cristian 13
Zerres, Klaus 86
Zhang, Dandan S2.3, S2.5, S5.3,
98, 127, 180
Zhang, Haitao S13.1
Zhang, Jian-Ping S9.3
Zhang, Michelle O10.2
Zhang, Peng 157
Zhang, Rui 204
Zhang, Yaoyang S6.1
Zhang, Ying 130
Zhang, Zhao O6.1
Zhang-James, Yanli S8.1, S8.3
Zhao, Hongyu ECI 16
Zhao, Qian O6.1, O7.1
Zhao, XinZhi O6.1
Zhao, Zhongming O2.6, O3.5, ECI 3,
42, 223, 266, 267
Zhong, Nan-Nan 204
Zhou, Kaixin 11
Zhou, Qiang O13.1
Zhou, Zhifeng O1.7
Ziaolhagh, Ali 158
Zimmer, Andreas O12.2, 120
Zimmermann, Petra O15.1, 100, 101
Zimmermann, Ulrich
S.
197
Zitman, Frans 60, 147
Zlojutro, Mark S12.5, 76
Zoë, Prichard 178
Zohar, Joseph 140
Zollner, Sebastian 157
Zubaid, Mohammed O10.2
Zuchner, Stephan O3.3
Zupanc, Tomaz 49
Zwiers, Marcel 2