Identification of New Genetic Risk Variants for Type 2 Diabetes

Abstract

Although more than 20 genetic susceptibility loci have been reported for type 2 diabetes (T2D), most reported variants have small to moderate effects and account for only a small proportion of the heritability of T2D, suggesting that the majority of inter-person genetic variation in this disease remains to be determined. We conducted a multistage, genome-wide association study (GWAS) within the Asian Consortium of Diabetes to search for T2D susceptibility markers. From 590,887 SNPs genotyped in 1,019 T2D cases and 1,710 controls selected from Chinese women in Shanghai, we selected the top 2,100 SNPs that were not in linkage disequilibrium (r²in silico replication in three T2D GWAS conducted among European Americans, Koreans, and Singapore Chinese. The 5 most promising SNPs were genotyped in an independent set of 1,645 cases and 1,649 controls from Shanghai, and 4 of them were further genotyped in 1,487 cases and 3,316 controls from 2 additional Chinese studies. Consistent associations across all studies were found for rs1359790 (13q31.1), rs10906115 (10p13), and rs1436955 (15q22.2) with P-values (per allele OR, 95%CI) of 6.49×10⁻⁹ (1.15, 1.10–1.20), 1.45×10⁻⁸ (1.13, 1.08–1.18), and 7.14×10⁻⁷ (1.13, 1.08–1.19), respectively, in combined analyses of 9,794 cases and 14,615 controls. Our study provides strong evidence for a novel T2D susceptibility locus at 13q31.1 and the presence of new independent risk variants near regions (10p13 and 15q22.2) reported by previous GWAS. Type 2 diabetes, a complex disease affecting more than a billion people worldwide, is believed to be caused by both environmental and genetic factors. Although some studies have shown that certain genes may make some people more susceptible to type 2 diabetes than others, the genes reported to date have only a small effect and account for a small proportion of type 2 diabetes cases. Furthermore, few of these studies have been conducted in Asian populations, although Asians are known to be more susceptible to insulin resistance than people living in Western countries, and incidence of type 2 diabetes has been increasing alarmingly in Asian countries. We conducted a multi-stage study involving 9,794 type 2 diabetes cases and 14,615 controls, predominantly Asians, to discover genes related to susceptibility to type 2 diabetes. We identified 3 genetic regions that are related to increased risk of type 2 diabetes.