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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.

Original publication

DOI

10.2337/db12-0406

Type

Journal article

Journal

Diabetes

Publication Date

03/2013

Volume

62

Pages

977 - 986

Addresses

Genomics and Molecular Medicine Unit, Council for Scientific and Industrial Research-Institute of Genomics and Integrative Biology, Delhi, India.

Keywords

DIAGRAM, INDICO, Chromosomes, Human, Pair 2, Humans, Diabetes Mellitus, Type 2, Insulin Resistance, Genetic Predisposition to Disease, Membrane Proteins, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Aged, Middle Aged, Asian Continental Ancestry Group, European Continental Ancestry Group, India, Genome-Wide Association Study, Genetic Loci