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

Nature Genetics volume 43, pages 984989 (2011) | Download Citation

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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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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.

Author information

Author notes

    • Jaspal S Kooner
    • , Danish Saleheen
    • , Xueling Sim
    • , Joban Sehmi
    • , Weihua Zhang
    • , Philippe Frossard
    • , Paul Elliott
    • , Yik Ying Teo
    • , Mark I McCarthy
    • , John Danesh
    • , E Shyong Tai
    •  & John C Chambers

    These authors contributed equally to this work.

Affiliations

  1. National Heart and Lung Institute (NHLI), Imperial College London, Hammersmith Hospital, London, UK.

    • Jaspal S Kooner
    • , Joban Sehmi
    • , Xinzhong Li
    •  & James Scott
  2. Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK.

    • Jaspal S Kooner
    • , Joban Sehmi
    • , Debashish Das
    •  & John C Chambers
  3. Imperial College Healthcare NHS Trust, London, UK.

    • Jaspal S Kooner
    •  & John C Chambers
  4. Center for Non-Communicable Diseases Pakistan, Karachi, Pakistan.

    • Danish Saleheen
    • , Philippe Frossard
    • , Asif Rasheed
    • , Maria Samuel
    •  & Nabi Shah
  5. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Danish Saleheen
    • , Robin Young
    •  & John Danesh
  6. Centre for Molecular Epidemiology, National University of Singapore, Singapore.

    • Xueling Sim
    • , Kee-Seng Chia
    • , Chiea-Chuen Khor
    • , Wei-Yen Lim
    • , Chen Suo
    •  & Yik Ying Teo
  7. Epidemiology and Biostatistics, Imperial College London, London, UK.

    • Weihua Zhang
    • , Paul Elliott
    •  & John C Chambers
  8. Department of Pediatrics, Section of Genetics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

    • Latonya F Been
    •  & Dharambir K Sanghera
  9. Department of Epidemiology and Public Health, National University of Singapore, Singapore.

    • Kee-Seng Chia
    • , Yik Ying Teo
    •  & E Shyong Tai
  10. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

    • Antigone S Dimas
    •  & Alexandra C Nica
  11. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Antigone S Dimas
    • , Åsa K Hedman
    • , Andrew P Morris
    • , Inga Prokopenko
    •  & Mark I McCarthy
  12. Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.

    • Neelam Hassanali
    • , David R Matthews
    • , Prasad Katulanda
    •  & Mark I McCarthy
  13. Department of Community Health Sciences, Aga Khan University, Karachi, Pakistan.

    • Tazeen Jafar
    •  & Muhammed Islam
  14. Department of Medicine, Aga Khan University, Karachi, Pakistan.

    • Tazeen Jafar
  15. Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.

    • Jeremy B M Jowett
    • , Malene M Kristensen
    •  & Paul Z Zimmet
  16. Department of Molecular Genetics, Madras Diabetes Research Foundation–Indian Council of Medical Research (ICMR) Advanced Centre for Genomics of Diabetes, Chennai, India.

    • Venkatesan Radha
    • , Manickam Chidambaram
    • , Samuel Liju
    •  & Viswanathan Mohan
  17. College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

    • Simon D Rees
    • , Anthony H Barnett
    •  & M Ann Kelly
  18. BioMedical Research Centre, Heart of England NHS Foundation Trust, Birmingham, UK.

    • Simon D Rees
    • , Anthony H Barnett
    •  & M Ann Kelly
  19. Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

    • Fumihiko Takeuchi
    •  & Norihiro Kato
  20. Department of Ophthalmology, National University of Singapore, Singapore.

    • Tin Aung
    •  & Tien Yin Wong
  21. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

    • Tin Aung
    • , Chiea-Chuen Khor
    •  & Tien Yin Wong
  22. Baqai Institute of Diabetology and Endocrinology, Karachi, Pakistan.

    • Abdul Basit
    •  & Zafar I Hydrie
  23. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Elin Grundberg
    •  & Kerrin S Small
  24. Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.

    • Chiea-Chuen Khor
    • , Jianjun Liu
    •  & Yik Ying Teo
  25. Ministry of Health, Port Louis, Mauritius.

    • Sudhir Kowlessur
  26. Department of Public Health, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.

    • Janani M Pinidiyapathirage
    •  & Ananda R Wickremasinghe
  27. Diabetic Association Pakistan, Karachi, Pakistan.

    • A Samad Shera
  28. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Kerrin S Small
  29. Center for Eye Research Australia, University of Melbourne, Melbourne, Victoria, Australia.

    • Tien Yin Wong
  30. Beijing Genomics Institute, Shenzhen, China.

    • Mingyu Yang
    • , Fan Zhang
    •  & Junbin Liang
  31. Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

    • Goncalo R Abecasis
  32. Clinical Pharmacology and Barts and the London Genome Centre, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.

    • Mark Caulfield
  33. Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Panos Deloukas
  34. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter, UK.

    • Timothy M Frayling
  35. Genomics of Common Diseases, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK.

    • Philippe Froguel
  36. Diabetes Research Unit, Department of Clinical Medicine, University of Colombo, Colombo, Sri Lanka.

    • Prasad Katulanda
  37. Dr Mohan's Diabetes Specialties Centre, Chennai, India.

    • Viswanathan Mohan
  38. Institute of Human Genetics, University of California, San Francisco, California, USA.

    • Mark Seielstad
  39. Medical Research Council (MRC)-Health Protection Agency (HPA) Centre for Environment and Health, Imperial College London, London, UK.

    • Paul Elliott
  40. Department of Statistics and Applied Probability, National University of Singapore, Singapore.

    • Yik Ying Teo
  41. National University of Singapore Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore.

    • Yik Ying Teo
  42. Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  43. Department of Medicine, National University of Singapore, Singapore.

    • E Shyong Tai
  44. Duke-National University of Singapore Graduate Medical School, Singapore.

    • E Shyong Tai

Consortia

  1. DIAGRAM

    A list of members is provided in the Supplementary Note.

  2. MuTHER

    A list of members is provided in the Supplementary Note.

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jaspal S Kooner or John C Chambers.

Supplementary information

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https://doi.org/10.1038/ng.921

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