2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
selected to be matched for age, gender and with subjects with T1DM
patients . All subjects selected for this study were unrelated Romanian
Caucasians . DNA samples were used for genotyping LECAM-1 P213S
polymorphism using restriction of amplicons with Hph1 endonuclease
.
The distribution of LECAM P213S in all lots is in agreement with Hardy
- Weinberg equilibrium . When compare the distribution of LECAM
genotypes in patients and control lots we observed only a trend of association
with ESRD in T1DM patients . The sex or age at ESRD onset
seems to not modify these observations . The lack of association with
ESRD in T2DM seems to be not similar with results reported for other
populations .
In conclusion, our study showed only a trend of association between
LECAM P213S polymorphism and IRC in DM 1 patients .
P06.083
On the choice of an exposure to test for gene-environment
interactions in type 2 diabetes: A new genotype-free method!
R. Kazma 1,2 , C. Bonaïti-Pellié 3,1 , J. M. Norris 4 , E. Génin 2,1 ;
1 Univ Paris-Sud, Paris, France, 2 INSERM U794, Paris, France, 3 INSERM UMR-
S535, Villejuif, France, 4 Department of Preventive Medicine and Biometrics,
University of Colorado Denver, Denver, CO, United States.
Gene-environment interactions might be involved in the susceptibility
to multifactorial diseases but are difficult to detect. Available methods
to test for gene-environment interactions usually concentrate on some
particular genetic and environmental factors . Rather than focusing on
a known genetic factor, we applied a new method to determine whether
or not a given exposure is susceptible to interact with unspecified genetic
factors, using the degree of familial aggregation as a surrogate .
The Odds Recurrence Ratio (ORR) is an indirect measure of interaction
since it contrasts recurrence risks in sibs of affected indexes when
stratifying on the exposure of indexes . A Wald chi-square test based
on the estimate of the ORR and its variance tests for the gene-environment
interaction, while accounting for a possible confounding bias if
indexes and their sibs are correlated for the exposure . An application
on a sample of 588 nuclear families ascertained through one index
affected with type 2 diabetes is presented where gene-environment interactions
involving obesity, physical activity and dietary fat intake are
investigated . An association with obesity is clearly evidenced and a potential
interaction involving this factor is suggested (p=0 .06) . Multiple
sibships have been used to increase sample size but a permutation
procedure is needed to account for dependency of sibpairs . Results
of this undergoing work will also be presented . The method proposed
here might be of particular interest prior to genetic studies to help determine
the environmental risk factors that will need to be accounted
for and select the most appropriate samples to genotype .
P06.084
compound heterozygosity in DJ- gene non-coding portion
related to parkinsonism
P. Tarantino 1 , D. Civitelli 1 , F. Annesi 1 , E. De Marco 1 , F. Rocca 1 , P. Pugliese 2 ,
G. Nicoletti 1,2 , I. Cirò Candiano 1 , S. Carrideo 1 , G. Provenzano 1 , G. Annesi 1 , A.
Quattrone 1,2 ;
1 Institute of Neurological Sciences, National Research Council, Mangone
(Csenza), Italy, 2 Institute of Neurology, Department of Medical Sciences, University
Magna Graecia, Catanzaro, Italy.
Mutations in DJ-1 gene cause a clinically characteristic autosomal
recessive juvenile onset form of Parkinson’s disease (PD) . We sequenced
the DJ-1 gene in 40 sporadic patients with early onset Parkinson’s
disease and 100 appropriate controls, originated from southern
Italy. We identified a single patient with age at onset of 38 years
carrying two novel heterozygous mutations, both located in non coding
regions. The first mutation (g. 159 C/G ), located in the promoter region,
was inherited from his mother whereas the second mutation , an
insertion in the intron 4 splice site (IVS4+3 insA), was transmitted from
his father . The DJ-1 cDNA level both in the patient and in a control subject
was normalized with the GAPDH gene and a significant reduction
(P= 0 .027) was found in the patient . Moreover, we obtained a single
size of DJ-1 cDNA fragments in both wild type and mutated individuals .
Of interest, no family member carrying only one of the two new mutations
manifested symptoms of EOPD . Genomic rearrangements were
excluded . Both mutations were absent in 200 control chromosomes .
In the remaining PD patients, we did not detect any pathogenic DJ-1
mutation. Our findings indicate that the mutant alleles are expressed
at a lowered level, or that their corresponding mRNAs are partially
degraded. Although the finding of a single size cDNA fragment is not
suggestive of the activation of any alternative cryptic splice site, this
cannot be fully excluded . Further studies are in progress .
P06.085
A genome-wide association study in schizophrenia using DNA
pooling on 574 parent-offspring trios
G. Kirov1 , I. Zaharieva1 , L. Georgieva1 , V. Moskvina1 , I. Nikolov1 , M. Owen1 , M.
O’Donovan1 , S. Cichon2 , A. Hillmer2 , D. Toncheva3 ;
1 2 Cardiff University, Cardiff, United Kingdom, University of Bonn, Bonn, Germany,
3University Hospital “Maichin Dom”, Sofia, Bulgaria.
We conducted a genomewide association study (GWAS) on schizophrenia
with DNA pooling in order to reduce the cost of the project . We
used a parent-offspring trios design in order to avoid the potential problems
of population stratification. We constructed pools from 605 unaffected
controls, 574 SZ patients and a third pool from all the parents
of the patients . We hybridised each pool 8 times on Illumina Human-
Hap550 arrays . We estimated the allele frequencies of each pool from
the averaged intensities of the arrays. The significance level of results
in the trios sample was estimated on the basis of the allele frequencies
in cases and non-transmitted pseudocontrols, taking into account the
technical variability of the data . We selected for individual genotyping
the highest-ranked SNPs, after excluding poorly performing SNPs and
those that showed a trend in the opposite direction in the control pool .
We genotyped 63 SNPs in 574 trios and analysed the results with the
transmission disequilibrium test (TDT). 40 of those were significant at
p