Evolutionary history of disease-susceptibility loci identified in longitudinal exome-wide association studies

Our longitudinal exome-wide association studies previously detected various genetic determinants of complex disorders using ~26,000 single-nucleotide polymorphisms (SNPs) that passed quality control and longitudinal medical examination data (mean follow-up period, 5 years) in 4884-6022 Japanese subjects. We found that allele frequencies of several identified SNPs were remarkably different among four ethnic groups. Elucidating the evolutionary history of disease-susceptibility loci may help us uncover the pathogenesis of the related complex disorders.

In the present study, we conducted evolutionary analyses such as extended haplotype homozygosity, focusing on genomic regions containing disease-susceptibility loci and based on genotyping data of our previous studies and datasets from the 1000 Genomes Project.

Our evolutionary analyses suggest that derived alleles of rs78338345 of GGA3, rs7656604 at 4q13.3, rs34902660 of SLC17A3, and six SNPs closely located at 12q24.1 associated with type 2 diabetes mellitus, obesity, dyslipidemia, and three complex disorders (hypertension, hyperuricemia, and dyslipidemia), respectively, rapidly expanded after the human dispersion from Africa (Out-of-Africa). Allele frequencies of GGA3 and six SNPs at 12q24.1 appeared to have remarkably changed in East Asians, whereas the derived alleles of rs34902660 of SLC17A3 and rs7656604 at 4q13.3 might have spread across Japanese and non-Africans, respectively, although we cannot completely exclude the possibility that allele frequencies of disease-associated loci may be affected by demographic events.

Our findings indicate that derived allele frequencies of nine disease-associated SNPs (rs78338345 of GGA3, rs7656604 at 4q13.3, rs34902660 of SLC17A3, and six SNPs at 12q24.1) identified in the longitudinal exome-wide association studies largely increased in non-Africans after Out-of-Africa.