2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
P06.260
clinical and genetic analysis of a four-generation family with
autosomal dominant cerebellar ataxia
F. Annesi 1 , D. Italiano 2 , G. Provenzano 1 , A. Laganà 2 , P. Tarantino 1 , F. Pisani 2 ,
E. V. De Marco 1 , G. Annesi 1 , A. Quattrone 1,3 ;
1 National Research Council, Institute of Neurological Sciences, Mangone
(Cosenza), Italy, 2 Department of Neurosciences of Psychiatric and A., First
Neurology Clinic, University of Messina, Messina, Italy, 3 Institute of Neurology,
University Magna Graecia, Catanzaro, Italy.
Autosomal dominant cerebellar ataxias (SCAs) are a heterogeneous
group of neurodegenerative disorders characterized by imbalance,
dysarthria, progressive gait and limb ataxia which are variably associated
with other neurological signs . There are many distinct loci associated
to Mendelian forms of SCA, but only 15 genes have been
identified (SCA 1-8, 10, 12-14, 17, 27 and DRPLA). Molecular genetic
studies have shown that SCAs are caused by abnormal repeat expansions
and that the age at onset is inversely correlated with repeat
length . In the present study we conducted a genetic analysis of a SCA
family from southern Italy, that included 15 affected members over four
generations . The mean age at onset was 34 years with a strong evidence
of anticipation across generations . We performed a mutational
analysis searching for the most common SCA mutations and a linkage
analysis for known genetic loci . The LOD score values were calculated
using the LINKAGE program package, assuming an autosomal dominant
inheritance and a disease frequency of 1 to 100,000 . Penetrance
in each subject was assigned to five liability classes determined from
the age at onset . Pathological repeat expansions in the SCA 1, 2, 3,
6, 7, 8, 12, 17 and DRPLA genes were excluded . In addition, there
was no evidence of linkage to SCA5 and SCA14 loci . We are now
performing linkage analysis of remaining SCA known loci . The lack of
any association will lead a full genome wide scan in order to identify
the disease-related locus .
P06.261
Association analysis of 42 sNPs in the tsNAX and Disc1 genes
in schizophrenia and bipolar affective disorder in the Polish
population
P. M. Czerski 1 , A. Karpushova 2 , S. Herms 2 , P. Kapelski 3 , M. Wiłkość 4 , B. Godlewska
5 , M. Tomaszewska 4 , A. Leszczyńska-Rodziewicz 3 , J. Hauser 3 , J. Landowski
5 , A. Borkowska 4 , M. Rietschel 6 , M. M. Nöthen 2 , S. Cichon 2 ;
1 Poznan University of Medical Sciences, Laboratory of Psychiatric Genetics,
Poznan, Poland, 2 University of Bonn, Department of Genomics, Life & Brain
Centre, Bonn, Germany, 3 Poznan University of Medical Sciences, Department
of Psychiatry, Poznan, Poland, 4 Clinical Neuropsychology Unit, Nicolaus Copernicus
University Torun, Collegium Medicum, Bydgoszcz, Poland, 5 Medical University
of Gdansk, Department of Psychiatry, Gdansk, Poland, 6 Central Institute
of Mental Health, Division of Genetic Epidemiology in Psychiatry, Mannheim,
Germany.
Linkage between schizophrenia and chromosome 1q42 .2 markers has
been reported independently in different populations worldwide . This
region contains the gene TSNAX and Disrupted in Schizophrenia 1
(DISC1) which had been found to be disrupted by a balanced translocation
and to co-segregate with schizophrenia in a large Scottish
pedigree . Association studies investigating DISC1 single nucleotide
polymorphisms (SNPs) in a number of samples were promising but
not yet compelling .
In the present study, we aimed at investigating the possible contribution
of TSNAX and DISC1 variants on the pathogenesis of SCH and
bipolar affective disorder .
We investigated 42 SNPs, on the basis of previous association findings,
using MALDI-TOF mass spectrometry-based SNP genotyping
(Sequenom’s iPLEX technology) . The study sample comprised 501
DSM-IV diagnosed patients with schizophrenia, 418 DSM-IV diagnosed
patients with bipolar affective disorder and 530 controls - all
from the Polish population .
For single marker analysis DISC1 rs1615409 was associated with
schizophrenia at the allelic (p=0 .001) and genotypic (p=0 .002) level .
TSNAX rs1411776 showed an association with bipolar disorder and
schizophrenia at the allelic (p=0 .015, and p=0 .053 respectively), and
genotypic level (p=0 .038 for bipolar disorder) .
Our results provide evidence for the contribution of rs1615409 to
schizophrenia susceptibility (particularly in females - p=0 .0004), and
modest evidence for an involvement of rs1411776 in the predisposition
to both studied diseases . However, only one SNP association survived
correction for multiple testing - for rs1615409 in schizophrenia . More
detailed analyses, including haplotype and subgrouping according to
age at onset and family loading are currently underway and will be
presented .
P06.262
A common haplotype of DRD3 affected by recent positive
selection is associated with protection from schizophrenia
J. Costas 1 , N. Carrera 1 , E. Domínguez 2 , E. Vilella 3 , L. Martorell 3 , J. Valero 3 , A.
Gutiérrez-Zotes 3 , A. Labad 3 , Á. Carracedo 1,4 ;
1 Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela,
Spain, 2 BIOFARMA, Departament de Farmacology, University of Santiago de
Compostela, Santiago de Compostela, Spain, 3 Psychiatric Hospital Institut Pere
Mata. Faculty of Medicine. University Rovira i Virgili, Reus, Spain, 4 Genomic
Medicine Group, Institute of Legal Medicine, University of Santiago de Compostela,
and CIBERER, Santiago de Compostela, Spain.
Recently, two independent reports identified association between
haplotypes of the dopamine receptor (DRD3) gene and schizophrenia
using different sets of tagSNPs . One of the reports suggests the existence
of a common protective haplotype . A case-control association
study was conducted in 273 schizophrenic patients and 512 controls
from NE Spain . The characterization of the linkage disequilibrium patterns
between tagSNPs of the previous reports was determined to
allow for pooled analysis, comprising a total of 794 cases and 1078
controls . Searching for natural selection was done with tests based
on extended linkage disequilibrium around specific haplotypes. The
pooled analysis gives a strong statistical support for the existence
of the protective haplotype (Mantel-Haenszel chi-square P value =
0 .00227) . This haplotype is linked to another haplotype at the locus,
characterized by the Ser variant at the non-synonymous SNP rs6280,
who increased its frequency recently by natural selection . Therefore,
we can conclude that there is a DRD3 schizophrenia protective haplotype
that has reached intermediate frequency due to the action of
selection on a linked functional polymorphism. This finding reveals that
natural selection may play a role in the existence of common alleles
of susceptibility to schizophrenia, suggesting a new approach to find
susceptibility loci .
P06.263
Recent adaptive selection at mAOB and ancestral susceptibility
to schizophrenia
N. Carrera 1 , J. Sanjuán 2 , M. Moltó 3 , Á. Carracedo 1,4 , J. Costas 1 ;
1 Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela,
Spain, 2 Psychiatric Unit, Faculty of Medicine, Clinical Hospital, University of
Valencia, Valencia, Spain, 3 Department of Genetics, Faculty of Biology, University
of Valencia, Valencia, Spain, 4 Genomic Medicine Group, Institute of Legal
Medicine, University of Santiago de Compostela, and CIBERER, Santiago de
Compostela, Spain.
The ancestral susceptibility hypothesis has been proposed to explain
the existence of common susceptibility alleles . Some ancestral alleles,
reflecting ancient adaptations, may be poorly adapted to the more contemporary
environmental conditions giving rise to an increased risk
to suffer some common disorders . In order to test this hypothesis in
schizophrenia, we focus on monoamine oxidase B (MAOB) . This gene
is involved in deamination of several monoamines, including both xenobiotic
amines present in several foods, as well as neurotransmitters
such as dopamine . In addition, preliminary analysis based on phase I
HapMap data suggested that recent natural selection have acted on
this locus . We further explored the existence of this recent positive selection
using a test based on extension of linkage disequilibrium (LD) to
large distance at the specific selected haplotype taking data from Hap-
Map phase II, and searched for association of the ancestral haplotypes
to schizophrenia in a sample of 532 schizophrenic patients and 597
controls from Spain . Our analysis suggests the existence of a haplotype
of MAOB subject to recent selection . In agreement with the ancestral
susceptibility hypothesis, the ancestral haplotypes were significantly
over-represented in patients (P = 0 .047) . These haplotypes confer an
increased risk to schizophrenia, restricted to males (P = 0 .024, OR =
1 .41, 95% CI 1 .01-1 .90) . Thus, pending on replication studies, MAOB
seems to fit the ancestral susceptibility model, opening a new strategy
to search for common schizophrenia susceptibility genes by focusing in
those functional candidate genes subject to recent positive selection .