Confirmation of multiple risk loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population

Abstract

OBJECTIVE-To identify novel type 2 diabetes gene variants and confirm previously identified ones, a three-staged genomewide association study was performed in the Japanese population. RESEARCH DESIGN AND METHODS-In the stage 1 scan, we genotyped 519 case and 503 control subjects with 482,625 single nucleotide polymorphism (SNP) markers; in the stage 2 panel comprising 1,110 case subjects and 1,014 control subjects, we assessed 1,456 SNPs (P < 0.0025, stage 1); additionally to direct genotyping, 964 healthy control subjects formed the in silico control panel. Along with genome-wide exploration, we aimed to replicate the disease association of 17 SNPs from 16 candidate loci previously identified in Europeans. The associated and/or replicated loci (23 SNPs; P < 7 × 10-5 for genome-wide exploration and P < 0.05 for replication) were examined in the stage 3 panel comprising 4,000 case subjects and 12,569 population-based samples, from which 4,889 nondiabetic control subjects were preselected. The 12,569 subjects were used for overall risk assessment in the general population. RESULTS-Four loci-1 novel with suggestive evidence (PEPD on 19q13, P = 1.4 × 10-5) and three previously reported - were identified; the association of CDKAL1, CDKN2A/CDKN2B, and KCNQ1 were confirmed (P < 10-19). Moreover, significant associations were replicated in five other candidate loci: TCF7L2, IGF2BP2, SLC30A8, HHEX, and KCNJ11. There was substantial overlap of type 2 diabetes susceptibility genes between the two populations, whereas effect size and explained variance tended to be higher in the Japanese population. CONCLUSIONS-The strength of association was more prominent in the Japanese population than in Europeans for more than half of the confirmed type 2 diabetes loci. © 2009 by the American Diabetes Association.