2008 Barcelona - European Society of Human Genetics

Normal variation, population genetics, genetic epidemiology
P06.325
Further support for the contribution of the NRG1 gene (8p12p21)
to the risk for schizophrenia: case-control association
study in a German population based on the GRAs Data
collection (Goettingen Research Association for schizophrenia)
S. Papiol 1 , M. Begemann 2 , H. Krampe 2 , S. Klaus 2 , F. Benseler 3 , S. Sperling 2 , S.
Stawicki 2 , K.A. Nave 1 , H. Ehrenreich 2 ;
1 Neurogenetics Department, 2 Division of Clinical Neuroscience and 3 Molecular
Neurobiology Department, Max Planck Institute of Experimental Medicine,
Hermann-Rein-Strasse 3, D-37075 Goettingen, Germany.
Background: Schizophrenia is a severe neuropsychiatric disorder with
a worldwide prevalence of around 1% and outstanding heritability estimates
(80%; Cardno & Gottesman, 2000) . The neuregulin 1 gene
(8p12-p21) has been strongly associated with an increased risk to
develop schizophrenia by numerous studies in several human populations
since the first association reported in an Icelandic population
(Stefansson et al ., 2002) . However this prominent genetic risk factor
has not been analyzed in the German population so far .
Methods: Authors analyzed the genetic variability contained in the «Icelandic
core-at-risk» haplotype as well as in the intron 1 of the NRG1
gene in a sample of German origin based on the GRAS Data Collection
(Goettingen Research Association for Schizophrenia), made up of 883
DSM-IV-diagnosed schizophrenic patients and 880 healthy controls,
in the context of a case-control study . SNPs were genotyped through
melting curve analysis in a LightCycler®480 system while microsatellite
analyses were carried out in a 3730xl DNA Analyzer® . Haplotype
analyses were performed using UNPHASED (Dudbridge, 2006) and
PHASE (Stephens et al ., 2001) .
Results: Sliding windows analysis revealed that the frequency of a
haplotypic combination defined by markers SNP8NRG241930, 487-2
and D8S1810 (G-12-18) was increased in cases (7 .9%) with respect
to controls (3.8%), and was significantly associated with an increased
risk for the disorder (P-value=7 .0x10-7; OR=2 .21 95%CI(1 .60-3 .08)) .
Conclusions: Our results reinforce the interest in the NRG1 gene as a
risk factor with a moderate but robust contribution to the risk for schizophrenia
.
Acknowledgements: Grant support from the Max-Planck Society and
the Deutsche Forschungsgemeinschaft (CMPB) . S . Papiol was supported
by a postdoctoral fellowship of the Spanish MEC .
P06.326
Population-based linkage analysis of schizophrenia case-control
cohorts identifies a potential susceptibility locus on 19q13
C. Francks 1 , P.Muglia 1 , D. Rujescu 2 , D. St Clair 3 ;
1 Medical Genetics, GlaxoSmithKline, Via Fleming 4, Verona 37135, Italy., 2 Division
of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University,
Munich, Germany, 3 Department of Mental Health,
University of Aberdeen, Aberdeen, UK.
Population-based linkage analysis is a novel method for analysing
genomewide SNP genotype data in case-control samples that does
not assume a common-disease, common-variant model . The genome
is scanned for increased identity-by-descent sharing of extended genomic
segments within case-case pairs, relative to case-control or
control-control pairs . The method is robust to allelic heterogeneity and
is suited to mapping genes which contain multiple, rare susceptibility
variants of relatively high penetrance . The method has been proposed
by Purcell et al . (Am J Hum Genet 2007) and implemented in the software
PLINK .
We analysed genomewide SNP genotype datasets for two schizophrenia
case-control cohorts, collected in Aberdeen (461 cases, 459
controls) and Munich (429 cases, 428 controls) . This analysis must be
performed within homogeneous samples and it was therefore necessary
to analyse the cohorts separately. Each cohort was first subjected
to several procedures to improve genetic homogeneity, including identity-by-state
outlier detection and multidimensional scaling analysis .
Using the complete cohorts there was no significant overlap in signals
between the Munich and Aberdeen cohorts . However, when testing
only those cases with a positive family history of major psychiatric disease,
which would fit better with a model of strongly penetrant susceptibility
alleles, we saw a distinct peak on chromosome 19q in both
samples (spanning the gene APOE but many others too), that appears
in meta-analysis (P=0 .000016) to be around the traditional level for
calling genomewide significance for linkage.
P07. Normal variation, population genetics,
genetic epidemiology
P07.001
DNA analysis for blood group ABO determination and RhD DNA
typing for prenatal diagnosis
A. V. Kirov, T. Todorov, A. Todorova;
Genetic laboratory Genica, Sofia, Bulgaria.
Blood type group can be determined immunologically or by genetic
methods, but genetic methods are more accurate .
We report on a method for ABO and RhD blood type determination,
performed by multiplex PCR and PCR-SSP (sequence-specific primers)
. These analyses provide fast, cheap and easy to perform method
for blood type determination . We utilize two PCR reactions for RhD
determination - first amplification covers the fragment spanning the
intron 3/intron 4 of RhD gene to look for 37bp insert in exon 4 . Second
PCR is multiplex (3 fragments), it amplifies intron 7 and 3’UTR of RhD
locus . Until now we have already done 14 prenatal diagnoses in RhD
(-) mothers . The obtained results for the fetuses RhD blood type were:
13 RhD positive and 1 RhD negative .
Determination of ABO blood type includes 4 specific regions analyzed
by PCR-SSP . Until now we have tested this method only using control
DNA probes to detect the method specificity and sensitivity. The
obtained results are promising and the method could be applied routinely
for ABO blood group determination . Both methods for DNA blood
group/RhD typing will be applied for the purposes of the individual
identification and paternity testing, as such analysis is in some cases
requested simultaneously with the DNA genotyping of the individuals .
P07.002
The ACE I/D polymorphism in Lithuanian professional athletes
V. Ginevičienė 1,2 , J. Kasnauskienė 1 , V. Kučinskas 1 ;
1 Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University,
Vilnius, Lithuania, 2 Lithuanian Olympic Sports Centre, Vilnius, Lithuania.
Human physical performance is under strong influence of genetic factors
. I/D polymorphism in the human angiotensin-1-coverting enzyme
(ACE) gene characterised by the presence (I allele) or absence (D
allele) of a 287-base-pair Alu repeat within intron 16 is among most
extensively investigated ones with respect to ACE activity and its involvement
in various pathophysiological conditions related to endurance.
Nevertheless, the results are still conflicting across studies and
populations . In the present study, ACE gene I/D polymorphism was
investigated in 413 Lithuanian professional athletes representing four
functional groups [endurance (N=57); mixed sports (N=44); strength
and speed (N=30), and team sports (N=282)], as well as in 120 samples
from general population of Lithuanians. Statistically significantly
higher D allele frequencies were found in strength and speed group
(P=0 .02) as well as in endurance group (P=0 .06), contrary to the prevailing
data from other studies showing association of endurance with I
allele . D allele also appeared to be more frequent in the general population
of Lithuanians (60,4 %) in comparison to the majority of other
European populations (30-50%) . Thus, increased D allele prevalence
in strength and speed group of athletes from Lithuania can be a reflection
of population frequency of this allele . In conclusion, our results
imply that the role of ACE gene I/D polymorphism in athletic performance
is not straightforward and can be masked by other genetic and
non-genetic factors .
P07.003
Association of the ActN3 gene variant with endurance athlete
status
A. M. Druzhevskaya, I. I. Ahmetov, I. V. Astratenkova, V. A. Rogozkin;
St Petersburg Research Institute of Physical Culture, St Petersburg, Russian
Federation.
Alpha-actinin-3 (ACTN3) is a myofibrillar protein found in fast-twitch
glycolytic muscle fibers. The less common X-allele of the R577X polymorphism
in the ACTN3 gene results in a premature stop codon and
alpha-actinin-3 protein deficiency in XX homozygotes. A strong association
has been reported between the R577X polymorphism and elite
athletic performance . The aim of the study was to investigate genotype
and allele distribution of ACTN3 gene in endurance-oriented athletes
and controls . The study involved 501 athletes (biathletes; rowers; long