PATTERN OF LD AND HAPLOTYPE DIVERSITY OF THE SCN1A GENE AS A BASIS FOR ASSOCIATION STUDIES IN EPILEPSY
Abstract number :
3.091
Submission category :
Year :
2002
Submission ID :
1959
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Chantal A.P. Depondt, Mike E. Weale, Stuart J. Macdonald, Alice C. Smith, David B. Goldstein, Nick W. Wood, Simon D. Shorvon. Molecular Pathogenesis, Institute of Neurology, London, United Kingdom; Biology, University College London, London, United Kingdo
RATIONALE: To establish an efficient genotyping strategy for association studies of susceptibility genes in epilepsy, based on knowledge of the pattern of linkage disequilibrium (LD) and haplotype diversity of the gene of interest.
METHODS: The first gene selected for this project was the neuronal sodium channel gene SCN1A, as this is a fairly large gene with an established role in Mendelian epilepsy and anti-epileptic drug responsiveness, and is thus considered a good candidate susceptibility gene for common epilepsy and/or drug sensitivity.
To identify single nucleotide polymorphisms (SNPs) in a 1700 kb genomic region around SCN1A, we sequenced 31 amplicons of 400-500 bp each. We subsequently typed all identified SNPs in 32 Chinese and 32 Malay trios (father, mother, child). Parental haplotypes were reconstructed from these data and haplotype diversity established. The pattern of LD in the gene region was assessed by P-values for Fisher[ssquote]s Exact Test on pairwise allele combinations. Finally, a small number of haplotype tag SNPs (htSNPs) for further genotyping in association studies was selected using r2 based criteria.
RESULTS: (see figure) : A total of 20 SNPs was identified, of which 14 were located within the SCN1A gene. Of these 20 SNPs, 7 were published at the time. Of the 13 SNPs from the dbSNP database (dbSNPs) amplified, only 6 proved to be polymorphic in our population. The entire gene appeared to be contained in one single block of LD.
For the 14 SNPs located within the gene, 13 different haplotypes were observed, of which 7 were shared by both population groups. Five common haplotypes accounted for respectively 92 and 82% of all haplotypes in the Chinese and Malay groups. Based on this information, we selected five htSNPs to type the SCN1A gene in large association studies, estimated to cover about 99% of all haplotype diversity.
CONCLUSIONS: 1. The knowledge of the pattern of LD and haplotype diversity of the SCN1A gene validates and greatly simplifies genotyping in association studies in epilepsy and anti-epileptic drug responsiveness.
2. We suggest this strategy should be used for genotyping of any candidate gene in association studies in epilepsy or other diseases.[figure1]
[Supported by: National Neuroscience Institute Singapore.
Genome Institute Singapore.]
