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

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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.

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Figure 1
Figure 2: Manhattan plot for the primary South Asian genome-wide association analysis of men and women using directly genotyped SNPs.
Figure 3: Regional plots for the six loci associated with type 2 diabetes in South Asians.

Change history

  • 16 September 2011

    In the version of this article initially published online, Elin Grundberg’s name was misspelled as Elin Grunberg, and Xinzhong Li’s name was misspelled as Xinzhing Li. The error has been corrected for the print, PDF and HTML versions of the article.

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Acknowledgements

We would like to thank the many colleagues who contributed to collection and phenotypic characterization of the clinical samples as well as genotyping and analysis of the GWAS data. We would also like to acknowledge those individuals who agreed to participate in these studies. Major funding for the work described in this paper comes from Wellcome Trust awards (070854/Z/03/Z, 080747/Z/06/Z, 083270/Z/07/Z, 084723/Z/08/Z); Chennai Wellingdon Corporate Foundation; Diabetes UK (07/0003512); National Institute for Health Research Comprehensive Biomedical Research Centre at Imperial College Healthcare NHS Trust; British Heart Foundation (SP/04/002); Medical Research Council (G0700931); National Institute for Health Research (RP-PG-0407-10371); US National Institutes of Health (DK-25446); KAKENHI (Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan; National Center for Global Health and Medicine; US National Institutes of Health (KO1TW006087); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082766); A*STAR Biomedical Research Council (05/1/21/19/425); Biomedical Research Council Singapore (09/1/35/19/616, 08/1/35/19/550); National Medical Research Council Singapore (NMRC/STaR/0003/2008, 1174/2008); National Science Foundation of Sri Lanka; and Oxford NIHR Biomedical Research Centre. A full list of acknowledgments is provided in the Supplementary Note.

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Manuscript preparation: J.S.K., D.S., X.S., J. Sehmi, W.Z., P.E., Y.Y.T., M.I.M., J.D., E.S.T. and J.C.C. wrote the manuscript. All authors read and provided critical comment on the manuscript. Data collection and analysis in the participating studies: COBRA study: T.J., M.I. and T.M.F. Chennai Urban Rural Epidemiology Study: V.R., M. Chidambaram, S.L. and V.M. Diabetes Genetics in Pakistan and UK Asian Diabetes Studies: S.D.R., A.B., Z.I.H., A.S.S., A.H.B. and M.A.K. London Life Sciences Population Study: J.S.K., W.Z., J. Sehmi, X.L., D.D., G.R.A., J. Scott, M. Caulfield, P. Froguel, P.E., M.I.M. and J.C.C. Mauritius study: J.B.M.J., S.K., M.M.K. and P.Z.Z. Pakistan Risk of Myocardial Infarction Study: D.S., P. Frossard, R.Y., A.R., M. Samuel, N.S., P.D. and J.D. Ragama Health Study: N.K., F.T., A.R.W. and J.M.P. Singapore Consortium of Cohort Studies: K.-S.C., W.-Y.L., C.-C.K., J. Liu and E.S.T. Sikh Diabetes Study: L.F.B. and D.K.S. Singapore Indian Eye Study: X.S., C.S., T.A., T.Y.W., M. Seielstad, Y.Y.T. and E.S.T. Sri Lankan Diabetes Study: N.H., I.P., D.R.M., P.K. and M.I.M. Sequencing of T2D loci: M.Y., F.Z., J. Liang, X.L., J.S.K. and J.C.C. Association results among Europeans in DIAGRAM: A.P.M. and M.I.M. eQTL analyses in MuTHER: A.S.D., E.G., Å.K.H., A.C.N., K.S.S. and M.I.M.

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Correspondence to Jaspal S Kooner or John C Chambers.

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A list of members is provided in the Supplementary Note.

A list of members is provided in the Supplementary Note.

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Kooner, J., Saleheen, D., Sim, X. et al. Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat Genet 43, 984–989 (2011). https://doi.org/10.1038/ng.921

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