2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
P06.087
Genetic effect of DAt1 and DRD2 gene polymorphisms on
personality traits in healthy individuals from Russia
A. Kazantseva 1 , D. Gaysina 1,2 , E. Khusnutdinova 1 ;
1 Institute of Biochemistry and Genetics Ufa Scientific Centre of Russian Academy
of Sciencies, Ufa, Russian Federation, 2 MRC SGDP Centre, Institute of
Psychiatry, King’s College, London, United Kingdom.
Psychobiological model proposed by Cloninger supposes that sociability
related personality traits are mediated by dopaminergic system
functioning. We aimed to define a single genotype effect of DRD2
TaqIA and DAT1 MspI polymorphisms and to check possible epistatic
effect between them and personality traits (assessed with the EPI and
TCI questionnaires) . 602 healthy individuals (men-206, women-396)
of Caucasian origin (Russians-214, Tatars-388) were recruited from
Russia (mean age±SD, 19 .85±2 .43 years) .
MANOVA (carried out with gender and ethnicity as second factors)
revealed the influence of DRD2*gender interaction on Novelty
Seeking (NS) (p=0 .017;F=5 .734) and Reward Dependence (RD)
(p=0 .039;F=4 .298) . Multiple comparisons explained this interaction
by the differences in NS and RD scores between female carriers of
A1-allele and male carriers of A2/A2-genotype (p=0 .001;F=11 .208 and
p=0 .000;F=16 .464 correspondingly); in NS scores between females
with A2/A2-genotype and males with A1-allele (p=0 .000;F=18 .678) .
Demonstrated effect could be partly due to higher NS and RD in
women compared to men (p=0 .000;F=26 .643 and p=0 .001;F=21 .102) .
Moreover, association of A1-allele with lower NS (p=0 .040;F=4 .278)
and higher RD (p=0 .029;F=4 .814) was demonstrated in men .
The effect of DAT1*ethnicity interaction was observed on RD
(p=0 .018;F=5 .615) caused by the differences in RD of G/G-genotype
carriers from Tatar and Russian population (p=0 .001;F=10 .752) . Association
between DAT1 A-allele carriers and higher extraversion
(p=0 .045;F=4 .030) and NS (p=0 .042;F=4 .148), lower Persistence
(p=0 .020;F=5 .401) was demonstrated .
Our findings suggest single DAT1 gene effect on extraversion and Persistence,
while differences in NS and RD are caused by DRD2*gender
and DAT1*ethnicity interaction .
This work was supported by RSCI grant 06-06-00163à and «Russian
Science Support Foundation» (to A .Kazantseva, D .Gaysina) .
P06.088
the t-Allele of the Dopamine transporter core Promoter
Polymorphism and Risk of Attention-Deficit Hyperactivity
Disorder
M. Ohadi 1 , A. Aghajani Refah 1 , E. Shirazi 2 , N. Moghimi 1 , H. Najmabadi 1 ;
1 Genetics Research Center , University of Social Welfare and Rehabilitation
Sciences, Tehran, Islamic Republic of Iran, 2 - Iran University of Medical Sciences,
Mental Health Research Center, Tehran, Islamic Republic of Iran.
Pharmacological and genetic findings implicate the DAT1 gene in the
development of attention-deficit/hyperactivity disorder. In this study,
we examined whether either allele of the DAT1 core promoter -67 functional
polymorphism is associated with ADHD in a case/control study .
The allele and genotype frequencies of the polymorphism were studied
in 110 patients and 120 controls, which were matched on the basis
of sex, age and ethnicity . The genotype frequencies in the patients
group were as follows: AA 19 .2%; AT 65 .2%; TT 15 .4% vs . the genotype
frequencies in the control group: AA 47 .5%; AT 43 .3%; TT 9 .2%
[χ 2 =20 .73, df = 2] The T-allele of the -67A/T polymorphism revealed a
~1 .56-fold excess in the patients group comparing with the controls
[χ 2 =14.50, df = 1].For the first time, these findings provide tentative
evidence of the contribution of the DAT1 gene core promoter polymorphism
to the etiopathophysiology of ADHD at least in the Iranian
population that we have studied. Further work is warranted to confirm
this finding and to assess its generalization to other ethnic groups.
P06.089
Origin of nondisjunction in trisomy 21 Down syndrome
S. K. Dey, S. Ghosh;
West Bengal University of Technology, Kolkata, India.
Down syndrome due to trisomy 21 is the most common human chromosomal
abnormality . In order to gain further insight into the mechanism
underlying nondisjunction, we investigated the association between
reduced recombination and nondisjunction .We genotyped 12
microsatellite markers spanning along 21q from centromere to telo-
mere in 122 individuals with free trisomy 21 and in their parents . Our
DNA marker studies of parental origin were informative in 119 families
with overwhelming majority 89 .91% being maternal and 10 .09% is paternal
. Only cases of maternal origin were included in our analysis .
The distribution of nondisjunction in maternal meiotic I and meiotic II
stages were 81 .19% and 19 .81% respectively . The mean maternal age
of nondisjunction in our Indian population sample is 27 .58±6 .4 which is
significantly lower than that of Caucasians.We created a genetic map,
using maternal meiotic I nondisjunction data . The female genetic map
was restricted to 21q .The distribution of chiasma shows a difference
throughout the length of chromosome arm(21q) with more recombination
towards telomeric end in comparison to control data . The telomeric
exchange is a significant risk factor for meiotic I nondisjunction,
irrespective of the age of the mother . Analysis of crossover events indicates
that in younger mother (< 29) there was an increase in both zero-
and one exchange events, suggesting reduction of recombination . The
linkage map of 21q(39.58cM) was significantly shorter than the control
female linkage map, indicating an overall reduction of recombination .
Thus, reduced recombination may be responsible , at least in part, for
the etiology of nondisjunction in trisomy 21 .
P06.090
Identification of a new locus for autosomal recessive
Dyschromatosis universalis hereditaria on chromosome 12q21q23
K. Brakensiek 1 , H. C. Hennies 2 , I. A. Bukhari 3 , G. Nürnberg 2 , C. Becker 2 ,
J. Huebener 1 , M. Cabrera Miranda 1 , H. Frye-Boukhriss 1 , S. Knothe 1 , J.
Schmidtke 1 , E. A. El-Harith 1 , M. Stuhrmann 1 ;
1 Institute of Human Genetics, Hannover Medical School, Hannover, Germany,
2 Cologne Center for Genomics, University of Cologne, Cologne, Germany,
3 Department of Dermatology, King Faisal University, Dammam, Saudi Arabia.
Background: Dyschromatoses are a group of pigmentary dermatoses
characterized by the presence of small and irregularly shaped hyper-
and hypopigmented maculae . There are two major forms of the disease:
Dyschromatosis symmetrica hereditaria (DSH), where the maculae
are restricted to the dorsal aspects of the extremities, and Dyschromatosis
universalis hereditaria (DUH), where patients are affected
by a generalized distribution of the maculae over most of their body .
Usually, both disorders show autosomal dominant inheritance, but in
some cases autosomal recessive inheritance was reported . Autosomal
dominant DSH was mapped to chromosome 1q21 .3, and mutations in
the ADAR- (DSRAD-) gene were identified. A second dyschromatosis
locus was mapped on chromosome 6q24 .2-q25 .2, but the two analyzed
families, which were initially reported to be affected with DSH,
were later suggested to have autosomal dominant DUH .
Patients and methods: We investigated whether one of the two known
Dyschromatosis-loci is involved in the development of DUH in a consanguineous
family from Saudi Arabia (four siblings were affected,
three siblings and the parents were unaffected) .
Results: After confirmation that neither of the two known loci is linked
to the disease in this family, a SNP-based genome-wide linkage analysis
was performed and a new locus for dyschromatosis was identified
on chromosome 12q21-q23 . The candidate region (LOD score of 3 .4)
contains 125 known or predicted genes .
Conclusion: We have identified a new locus for DUH, and obtained
evidence that DUH and DSH are distinct disorders with different genetic
origins .
P06.091
Frequency of the coding polymorphisms in the PARK2 gene
- characterization of the polish group with Parkinson disease of
the early onset
D. Hoffman-Zacharska1 , D. Koziorowski2 , J. Bal1 , A. Friedman2 ;
1Institute of Mother and Child, Dept. of Medical Genetics, Warsaw, Poland,
2Faculty of Health Science, Medical University in Warsaw, Dept. of Neurology,
Warsaw, Poland.
Parkinson disease (PD; OMIM 168600) is the second most frequent
neurodegenerative disease in the elderlity . Among the PD patients
there is less common group of age of onset before 50 years classified
as a early-onset PD (EO-PD) with mutations in parkin gene (PARK2;
OMIM 62544) as a common cause . The prevalence of this form of PD
is not known . However, in Europe, parkin type of EO-PD accounts for
approximately 50% of autosomal recessive parkinsonism and 18% of
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