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Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.

ABSTRACT: We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.

SUBMITTER: Kooner JS

PROVIDER: S-EPMC3773920 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.

Kooner Jaspal S JS Saleheen Danish D Sim Xueling X Sehmi Joban J Zhang Weihua W Frossard Philippe P Been Latonya F LF Chia Kee-Seng KS Dimas Antigone S AS Hassanali Neelam N Jafar Tazeen T Jowett Jeremy B M JB Li Xinzhong X Radha Venkatesan V Rees Simon D SD Takeuchi Fumihiko F Young Robin R Aung Tin T Basit Abdul A Chidambaram Manickam M Das Debashish D Grundberg Elin E Hedman Asa K AK Hydrie Zafar I ZI Islam Muhammed M Khor Chiea-Chuen CC Kowlessur Sudhir S Kristensen Malene M MM Liju Samuel S Lim Wei-Yen WY Matthews David R DR Liu Jianjun J Morris Andrew P AP Nica Alexandra C AC Pinidiyapathirage Janani M JM Prokopenko Inga I Rasheed Asif A Samuel Maria M Shah Nabi N Shera A Samad AS Small Kerrin S KS Suo Chen C Wickremasinghe Ananda R AR Wong Tien Yin TY Yang Mingyu M Zhang Fan F Abecasis Goncalo R GR Barnett Anthony H AH Caulfield Mark M Deloukas Panos P Frayling Timothy M TM Froguel Philippe P Kato Norihiro N Katulanda Prasad P Kelly M Ann MA Liang Junbin J Mohan Viswanathan V Sanghera Dharambir K DK Scott James J Seielstad Mark M Zimmet Paul Z PZ Elliott Paul P Teo Yik Ying YY McCarthy Mark I MI Danesh John J Tai E Shyong ES Chambers John C JC

Nature genetics 20110828 10

We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci ( ...[more]

PMID: 21874001

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Project description:Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ?3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10(-8). Suggestive (p<5×10(-7)) and genome-wide significant (p<5×10(-8)) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10(-10)). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10(-11)), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10(-19)). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10(-13)), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10(-10)). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

Dataset Information

Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.

Publications

Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.

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