2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
P06.299
Further evidence for association of the RGS gene with
antipsychotic-induced parkinsonism: Protective role of a
functional polymorphism in the 3’ untranslated region
E. Ben-Asher 1 , L. Greenbaum 2 , R. C. Smith 3,4 , A. Rigbi 2 , R. Strous 5 , O. Teltsh 2 ,
K. Kanyas 2 , M. Korner 2 , D. Lancet 1 , B. Lerer 2 ;
1 The Weizmann Institute of Science, Rehovot, Israel, 2 Hadassah-Hebrew University
Medical Center, Jerusalem, Israel, 3 New York University Medical School,
New York, NY, United States, 4 Manhattan Psychiatric Center, New York, NY,
United States, 5 Beer Yaakov Mental Health Cneter, Beer Yaakov, Israel.
In our previous study using a candidate gene approach we have shown
that the RGS2 gene (regulator of G protein signaling 2) is associated
with susceptibility to extrapyramidal symptoms (EPS) induced by antipsychotic
drugs (Pharmacogenet Genomics . 2007 Jul; 17(7):519-28) .
Thus supporting our hypothesis that since regulators of G protein signaling
(RGS) play a pivotal role in dopaminergic transmission, genetically
based, functional variation could influence therapeutic response
to antipsychotic drugs .
To further investigate our previous report we performed a replication
study . EPS were rated in U .S . patients with schizophrenia (African-
American and Caucasian) treated for at least a month with typical
antipsychotic drugs risperidone, olanzapine, or clozapine . Six single
nucleotide polymorphisms (SNPs) within or flanking RGS2 were genotyped.
Odds ratios and confidence intervals calculations indicate association
of SNP rs4606 with antipsychotic-induced parkinsonism (AIP)
in the overall sample and in the African-American sub-sample with the
minor allele having a protective effect . Sequence analysis of the RGS2
gene further indicated that this SNP is biologically meaningful and
could have clinical utility .
P06.300
UcP3 gene polymorphism and cardiac growth in response to 1
year of endurance training
S. B. Goriyeva 1 , I. I. Ahmetov 1,2 , O. L. Vinogradova 1 ;
1 SRC Institute for Biomedical Problems of the Russian Acad. Sci, Moscow,
Russian Federation, 2 St Petersburg Research Institute of Physical Culture, St
Petersburg, Russian Federation.
Reduced fatty acid utilization and increased oxidative stress both can
contribute to the development of cardiac hypertrophy . Left ventricular
hypertrophy in endurance-oriented athletes is generally understood to
be a limiting factor for improving maximal oxygen uptake (VO2max) .
Cardiac uncoupling protein 3 (UCP3) can serve to protect the heart
against lipid-induced oxidative stress, and stimulate fatty acid transport
and oxidation . A variant in the UCP3 gene associated with higher
mRNA levels has been identified (UCP3 -55C/T). This variant has
been associated with reduced risk of type 2 diabetes and obesity . Recently
we have shown that -55T allele was overrepresented in highly
elite rowers and was associated with high values of VO2max . If UCP3
is important for muscle and heart metabolism and can protect against
development of LVH, then one might anticipate -55T variant of UCP3
gene to be associated with insignificant cardiac growth (rational adaptation)
in response to endurance training . We have tested this hypothesis
in the study of elite Russian rowers (n=19, males) . UCP3 -55C/T
polymorphism was determined by PCR-RLFP . Echocardiography was
performed for two times with one year interval . We found that subjects
of CC genotype exhibited the greatest cardiac growth (when interventricular
septal wall thickness was measured; CC: 3 (1 .4) mm, CT: 1
(0) mm, TT: -1 mm; P=0 .019), whereas the individuals of TT genotype
exhibited the reduction in septal wall thickness . In conclusion, we demonstrate
that variation in the UCP3 gene influences cardiac growth in
response to endurance training in rowers .
P06.301
Powerful new methods for whole genome copy number
association studies
C. G. Lambert1 , G. F. Rudy1 , I. H. Lake1 , J. G. Grover1 , D. M. Hawkins2 ;
1 2 Golden Helix, Inc., Bozeman, MT, United States, School of Statistics, University
of Minnesota, Minneapolis, MN, United States.
The latest genotyping arrays provide over a million markers across
the genome to interrogate copy number variation (CNV), making it
possible to perform whole genome copy number association studies .
However, the various statistical and computational challenges involved
with the analysis of copy number data on such a large scale have pre-
vented such association studies from being completed . Instead, whole
genome copy number studies have been limited to paired sample
analysis or visual inspection on small numbers of samples . Arguably,
due to small sample sizes and the susceptibility of visual inspection to
human error, such approaches offer only cursory insights and lack in
their effectiveness to uncover CNV associations .
To address these issues, we developed a series of novel methods embodied
in a new tool called CNAM. CNAM is capable of efficiently and
accurately preprocessing whole genome copy number data for thousands
of samples, finding large to single probe CNVs, and performing
a range of statistical tests to identify CNV associations .
Discussed methods include accurately extracting log ratio signals,
quantile normalization without gender bias to properly normalize
against reference populations, optimal univariate and multivariate segmenting
based on dynamic programming (Hawkins Segmentation) to
determine regions of variation, enhanced Eigenstrat-based principal
component analysis to detect and correct for population stratification
and batch effects, and association testing using various copy number
measures as covariates .
We demonstrate the utility of these methods by presenting preliminary
results on public whole-genome data using thousands of case-control
samples .
P06.302
First case of maternal UPD7 and recessive congenital myotonia
C. Bulli 1 , C. Peconi 1 , P. Battistella 2 , M. Bordignon 3 , L. Salviati 3 , F. Sangiuolo 1 ,
G. Novelli 1 ;
1 Department of Biopathology, Tor Vergata University, Rome, Italy, 2 Department
of Pediatrics, Padua University, Padua, Italy, 3 Department of Clinical Genetics,
University of Padova, Padua, Italy.
Autosomal congenital myotonia dominant (Thomsen) and recessive
(Becker) are rare non dystrophic disorders due to allelic mutations of
the muscle chloride channel gene, CLCN1, located on chromosome
7q35 . Both diseases are characterised by muscle stiffness and myotonia,
which is based on an electrical instability of the muscle fibber
membrane, but they differ clinically by age at onset .
We report on the clinical and molecular data of the first case of a Becker
patient carrying two identical mutations because of a maternal UPD
of the entire chromosome 7 .
The proband is 14-year-old male with involuntarily prolonged contraction
of muscles, hypertrophy calves, normal CPK and EMG with dynamic
myotonia . Moreover he was reported as having severe growth
retardation and a facial anomalies compatible with the diagnosis of
Silver-Russell syndrome . Proband’s DNA analyses showed homozygosity
for a novel mutation leading to a G355R substitution (GGG→
AGG) . The mutation segregated only from the mother, while the father
was not carrier for G355R . Non paternity was excluded using a panel
of 15 highly polymorphic markers and one marker for amelogenin .
Only markers located on chromosome 7 showed some segregation
anomalies from the father. For this reason, a fluorescent microsatellite
analysis was performed using 9 polymorphic markers spanning the
entire chromosome 7 region . PCR products were analysed by automated
sequencer . All the markers showed homozygosity in proband’s
DNA. Our results clearly allowed us to affirm the presence of a maternal
isodisomy of the entire chromosome 7 (matUPD7) in the affected
proband .
P06.303
A genome wide association study reveals sLc2A9 as a major
gene for uric acid levels with pronounced gender-specific
effects
C. Gieger 1,2 , A. Döring 1 , D. Mehta 3 , H. Gohlke 1 , H. Prokisch 3,4 , S. Coassin 5 , G.
Fischer 1 , K. Henke 6 , N. Klopp 1,2 , F. Kronenberg 5 , B. Paulweber 7 , A. Pfeufer 3,4 ,
D. Rosskopf 6 , H. Völzke 8 , T. Illig 1 , T. Meitinger 3,4 , H. E. Wichmann 1,2 , C. Meisinger
1,9 ;
1 Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg/Munich,
Germany, 2 Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität,
Munich, Germany, 3 Institute of Human Genetics,
Helmholtz Zentrum München, Neuherberg/Munich, Germany, 4 Institute of Human
Genetics, Klinikum rechts der Isar, Technical University Munich, Munich,
Germany, 5 Division of Genetic Epidemiology, Department of Medical Genetics,
Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck,
Austria, 6 Department Pharmacology, Ernst-Moritz-Arndt University, Greifswald,