Original Research

Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India

  1. Richa Saxena1,
  2. Danish Saleheen2,3,4,
  3. Latonya F. Been5,
  4. Martha L. Garavito5,
  5. Timothy Braun5,
  6. Andrew Bjonnes1,
  7. Robin Young3,
  8. Weang Kee Ho3,
  9. Asif Rasheed2,
  10. Philippe Frossard2,
  11. Xueling Sim6,7,
  12. Neelam Hassanali8,
  13. Venkatesan Radha9,
  14. Manickam Chidambaram9,
  15. Samuel Liju9,
  16. Simon D. Rees10,11,
  17. Daniel Peng-Keat Ng12,
  18. Tien-Yin Wong13,14,15,
  19. Toshimasa Yamauchi16,
  20. Kazuo Hara16,17,
  21. Yasushi Tanaka18,
  22. Hiroshi Hirose19,
  23. Mark I. McCarthy8,20,21,
  24. Andrew P. Morris20,
  25. DIAGRAM*,
  26. MuTHER*,
  27. AGEN*,
  28. Abdul Basit22,
  29. Anthony H. Barnett11,
  30. Prasad Katulanda8,23,
  31. David Matthews8,
  32. Viswanathan Mohan9,24,
  33. Gurpreet S. Wander25,
  34. Jai Rup Singh26,
  35. Narinder K. Mehra27,
  36. Sarju Ralhan25,
  37. M. Ilyas Kamboh28,
  38. John J. Mulvihill5,
  39. Hiroshi Maegawa29,
  40. Kazuyuki Tobe30,
  41. Shiro Maeda31,
  42. Yoon S. Cho32,
  43. E. Shyong Tai12,33,34,
  44. M. Ann Kelly10,11,
  45. John C. Chambers35,36,37,
  46. Jaspal S. Kooner35,36,38,
  47. Takashi Kadowaki16,
  48. Panos Deloukas39,
  49. Daniel J. Rader40,
  50. John Danesh3 and
  51. Dharambir K. Sanghera5⇑
  1. 1Center for Human Genetic Research and Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
  2. 2Center for Non-Communicable Diseases, Karachi, Pakistan
  3. 3Department of Public Health and Primary Care, University of Cambridge, Cambridge, U.K.
  4. 4Departments of Biostatistics and Epidemiology and Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
  5. 5Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
  6. 6Center for Statistical Genetics and Department of Statistics, University of Michigan, Ann Arbor, Michigan
  7. 7Centre for Molecular Epidemiology, National University of Singapore, Singapore
  8. 8Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, U.K.
  9. 9Madras Diabetes Research Foundation, Chennai, India
  10. 10College of Medical and Dental Sciences, University of Birmingham, Birmingham, U.K.
  11. 11Diabetes Centre, Heart of England National Health Service Foundation Trust, Birmingham, U.K.
  12. 12Saw Swee Hock School of Public Health, National University of Singapore, Singapore
  13. 13Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
  14. 14Department of Ophthalmology, National University of Singapore, Singapore
  15. 15Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia
  16. 16Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  17. 17Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo, Japan
  18. 18Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kanagawa, Japan
  19. 19Health Center, Keio University School of Medicine, Tokyo, Japan
  20. 20Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
  21. 21Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
  22. 22Baqai Institute of Diabetology and Endocrinology, Karachi, Pakistan
  23. 23Diabetes Research Unit, Department of Clinical Medicine, University of Colombo, Colombo, Sri Lanka
  24. 24Dr. Mohan's Diabetes Specialities Centre, Chennai, India
  25. 25Hero Dayanand Medical College and Heart Institute, Ludhiana, Punjab, India
  26. 26Central University of Punjab, Bathinda, Punjab, India
  27. 27All India Institute of Medical Sciences and Research, New Delhi, India
  28. 28Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania
  29. 29Department of Medicine, Shiga University of Medical Science, Shiga, Japan
  30. 30First Department of Internal Medicine, University of Toyama, Toyama, Japan
  31. 31Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine, Kanagawa, Japan
  32. 32Department of Biomedical Science, Hallym University, Chuncheon, Gangwon-do 200-702, Republic of Korea
  33. 33Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  34. 34Duke-NUS Graduate Medical School Singapore, Singapore
  35. 35Ealing Hospital National Health Service Trust, Middlesex, U.K.
  36. 36Imperial College Healthcare National Health Service Trust, London, U.K.
  37. 37Epidemiology and Biostatistics, Imperial College London, London, U.K.
  38. 38National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, U.K.
  39. 39Wellcome Trust Sanger Institute, Hinxton, U.K.
  40. 40Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
  1. Corresponding author: Dharambir K. Sanghera, dharambir-sanghera{at}ouhsc.edu.
Diabetes 2013 May; 62(5): 1746-1755. https://doi.org/10.2337/db12-1077

Article Figures & Tables

Figures

  • FIG. 1.
    FIG. 1.

    Summary of study design and outcome of key findings.

  • FIG. 2.
    FIG. 2.

    A: Manhattan plot showing primary genome-wide association analysis of the Punjabi Sikh discovery cohort using directly genotyped (524,216) SNPs. B: Manhattan plot shows imputed 1,232,008 SNPs on the x-axis and −log10 P value of association on the y-axis. Locations of the three loci (including one novel locus at SGCG) reached genome-wide significance after combined analysis of the GWAS and replication data in Punjabi Sikhs.

  • FIG. 3.
    FIG. 3.

    A: Regional association plot for a new T2D locus detected at 13q12 in the SGCG gene from the genome-wide meta-analysis in Sikhs. B: A strong confirmation of SNPs in the TCF7L2 gene in Sikh meta-analysis. In these plots, the SNPs showing the most strongly associated signal are depicted as a red diamond with blue border for the combined stage 1, 2a, and 3a results for meta-analysis, and the red diamond with black border shows evidence of association for the stage 1 results. Each square in color shows a SNP with the color scale relating the r2 value for that SNP and the top SNP taken from the HapMap 3 GIH panel. We present LD using the GIH panel, the closest HapMap population to the Sikhs; however, we note that there could still be differential LD between the reference panel and the Sikh population. At the bottom of the plot, the locations of known genes in the region are shown.

  • FIG. 4.
    FIG. 4.

    Forest plot showing the association of lead SNP in the SGCG (rs9552911) gene with T2D. For each study, the estimates of the ORs with 95% CI are shown. In addition, meta-analyses of Sikhs and South Asians and multiethnic studies are shown at the bottom. Meta-analysis in Sikhs shows a significant association of rs9552911 with T2D (OR 0.67 [0.58–0.77], P = 1.82 × 10−8). The red diamond signifies the OR and CI across all multiethnic samples.

Tables

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Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India
Richa Saxena, Danish Saleheen, Latonya F. Been, Martha L. Garavito, Timothy Braun, Andrew Bjonnes, Robin Young, Weang Kee Ho, Asif Rasheed, Philippe Frossard, Xueling Sim, Neelam Hassanali, Venkatesan Radha, Manickam Chidambaram, Samuel Liju, Simon D. Rees, Daniel Peng-Keat Ng, Tien-Yin Wong, Toshimasa Yamauchi, Kazuo Hara, Yasushi Tanaka, Hiroshi Hirose, Mark I. McCarthy, Andrew P. Morris, DIAGRAM, MuTHER, AGEN, Abdul Basit, Anthony H. Barnett, Prasad Katulanda, David Matthews, Viswanathan Mohan, Gurpreet S. Wander, Jai Rup Singh, Narinder K. Mehra, Sarju Ralhan, M. Ilyas Kamboh, John J. Mulvihill, Hiroshi Maegawa, Kazuyuki Tobe, Shiro Maeda, Yoon S. Cho, E. Shyong Tai, M. Ann Kelly, John C. Chambers, Jaspal S. Kooner, Takashi Kadowaki, Panos Deloukas, Daniel J. Rader, John Danesh, Dharambir K. Sanghera
Diabetes May 2013, 62 (5) 1746-1755; DOI: 10.2337/db12-1077
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