Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21

Abstract

Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10⁻⁹). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10⁻¹²) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D.

FIG. 1.

Study design.

FIG. 2.

Manhattan plot of the association P values for T2D. The −log10 P values for association of directly genotyped SNPs are plotted as a function of genomic position (National Center for Biotechnology Information Build 37). The P values were determined using logistic regression adjusted for age, sex, PC1, and PC2 in stage 1 analysis. Each chromosome (Chr) has been represented with a unique color.

FIG. 3.

Regional plot of 2q21. Regional association plot depicting P value distribution of all genotyped and imputed SNPs in a 2-Mb region flanking the SNP rs6723108 (1 Mb each side) at chromosome 2q21. A: Stage 1 genotyped SNPs. B: Stage 1 genotyped and imputed SNPs. C: Stage 1 genotyped and imputed SNPs conditioned for rs6723108. Strength of pairwise LD between all SNPs and rs6723108 has been color-coded and, based on r², computed from present study data (stage 1). Recombination rates were estimated from HapMap2 combined panel.