Analysis of linkage disequilibrium and haplotype at the single -minded homology 2 locus in four populations, as a model for analysis of candidate loci in complex genetic disease.

摘要

Identifying variation in the human genome which is associated with complex genetic disease is perhaps the greatest challenge in human genetics today. We have investigated patterns of Linkage Disequilibrium (LD) and haplotype at the Single Minded Homologue 2 (SIM2) locus on human chromosome 21 in four populations, as a model system for association studies of candidate genes. Nine single nucleotide polymorphisms (SNPs) with heterozygosity greater than 30% in the CEPH Utah families were identified, spanning 25,000 base pairs (bp); the same nine polymorphisms were also genotyped in an Amish population, a Japanese population, and a Chinese population. SNP heterozygosities were similar globally. Analysis of LD patterns in the Amish vs. CEPH populations did not show a significantly greater extent of LD in the Amish, confirming theoretical predictions that founder populations do not provide additional power to detect disease associated polymorphisms which were frequent before the founding event. Analysis of LD vs. physical distance in bp shows a similar trend of LD with distance in all four populations.;Haplotype analysis of all 9 SNPs shows 57 haplotypes in 352 independent chromosomes globally, with the most frequent haplotype observed 24 times. Inspection of a 10 kbp subregion containing 6 SNPs showed a much more limited diversity of haplotype globally: 3 haplotypes (out of 26 = 32 possible haplotypes) account for 72% of all haplotypes globally, and account for greater than 66% of all 6 SNP haplotypes. These three frequent clades presumably represent truly ancient haplotypes, predating the divergence of the major non-African ethnic groups. We propose that identification of similar regions with limited haplotype diversity will facilitate identification of ancient, frequent haplotypes associated with complex genetic disease where such ancient associations exist.