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Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease

Nature Genetics volume 49, pages 1450–1457 (2017)Cite this article

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Abstract

To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D–CHD analysis identified eight variants—two of which are coding—where T2D and CHD associations appear to colocalize, including a new joint T2D–CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.

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Figure 1: A circular Manhattan plot summarizing the association results for the T2D scan.

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Acknowledgements

D.S. has received support from NHLBI, NINDS, Pfizer, Regeneron Pharmaceuticals, Genentech, and Eli Lilly. Genotyping in PROMIS was funded by the Wellcome Trust, UK, and Pfizer. Biomarker assays in PROMIS have been funded through grants awarded by the NIH (RC2HL101834 and RC1TW008485) and Fogarty International (RC1TW008485). The RACE study has been funded by NINDS (R21NS064908), Fogarty International (R21NS064908), and the Center for Non-Communicable Diseases (Karachi, Pakistan). B.F.V. was supported by funding from the American Heart Association (13SDG14330006), the W.W. Smith Charitable Trust (H1201), and the NIH/NIDDK (R01DK101478). J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and NIHR Senior Investigator. V.S. was supported by the Finnish Foundation for Cardiovascular Research. S. Ripatti was supported by the Academy of Finland (251217 and 255847), the Center of Excellence in Complex Disease Genetics, the European Union's Seventh Framework Programme projects ENGAGE (201413) and BioSHaRE (261433), the Finnish Foundation for Cardiovascular Research, Biocentrum Helsinki, and the Sigrid Juselius Foundation. The Mount Sinai IPM Biobank Program is supported by the Andrea and Charles Bronfman Philanthropies. S. Anand is supported by grants from the Canada Research Chair in Ethnic Diversity and CVD and from the Heart and Stroke Michael G. DeGroote Chair in Population Health, McMaster University. Data contributed by Biobank Japan were partly supported by a grant from the Leading Project of the Ministry of Education, Culture, Sports, Science and Technology, Japan. We thank the participants and staff of the Copenhagen Ischemic Heart Disease Study and the Copenhagen General Population Study for their important contributions. The CHD Exome+ Consortium was funded by the UK Medical Research Council (G0800270), the British Heart Foundation (SP/09/002), the UK NIHR Cambridge Biomedical Research Centre, the European Research Council (268834), the European Commission's Framework Programme 7 (HEALTH-F2-2012-279233), Merck, and Pfizer. PROSPER has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement HEALTH-F2-2009-223004.

Author information

Author notes

  1. Wei Zhao, Asif Rasheed and Emmi Tikkanen: These authors contributed equally to this work.

  2. Benjamin F Voight and Danish Saleheen: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Wei Zhao & Danish Saleheen

  2. Department of Medicine, Translational Medicine and Human Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Wei Zhao, Jung-Jin Lee, Kevin Trindade, Daniel J Rader & Danish Saleheen

  3. Center for Non-Communicable Diseases, Karachi, Pakistan

    Asif Rasheed, Nabi Shah, Sehrish Jabeen, Atif Imran, Faisal Majeed, Philippe Frossard & Danish Saleheen

  4. Department of Public Health, University of Helsinki, Helsinki, Finland

    Emmi Tikkanen & Samuli Ripatti

  5. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

    Emmi Tikkanen & Samuli Ripatti

  6. Department of Public Health and Primary Care, MRC/BHF Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, UK

    Adam S Butterworth, Joanna M M Howson, Rajiv Chowdhury, Praveen Surendran, Emanuele Di Angelantonio, Robin Young & John Danesh

  7. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

    Themistocles L Assimes & Thomas Quertermous

  8. Department of Clinical Sciences, Lund University, Malmö, Sweden

    Marju Orho-Melander & Olle Melander

  9. Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Scott Damrauer

  10. Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Aeron Small, Daniel J Rader & Benjamin F Voight

  11. Department of Mathematics and Statistics, McMaster University, Hamilton, Ontario, Canada

    Senay Asma

  12. Laboratory for Endocrinology, Metabolism, and Kidney Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    Minako Imamura & Shiro Maeda

  13. Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan

    Minako Imamura & Shiro Maeda

  14. Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Nishihara, Japan

    Minako Imamura & Shiro Maeda

  15. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Toshimasa Yamauch & Takashi Kadowaki

  16. Department of Epidemiology and Biostatistics, Imperial College London, London, UK

    John C Chambers, Weihua Zhang & Jaspal S Kooner

  17. Ealing Hospital NHS Trust, Southall, UK

    John C Chambers & Weihua Zhang

  18. Imperial College Healthcare NHS Trust, London, UK

    John C Chambers & Jaspal S Kooner

  19. Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore

    Peng Chen & Yik Ying Teo

  20. Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

    Bishwa R Sapkota & Dharambir K Sanghera

  21. Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan

    Nabi Shah

  22. Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Yingchang Lu, Erwin P Bottinger & Ruth J F Loos

  23. Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Yingchang Lu & Ruth J F Loos

  24. Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Yingchang Lu & Ruth J F Loos

  25. Faisalabad Institute of Cardiology, Faisalabad, Pakistan

    Shahid Abbas

  26. National Institute of Cardiovascular Disorders, Karachi, Pakistan

    Nadeem Qamar, Zia Yaqoob, Tahir Saghir, Syed Nadeem Hasan Rizvi & Anis Memon

  27. Punjab Institute of Cardiology, Lahore, Pakistan

    Nadeem Hayyat Mallick

  28. Karachi Institute of Heart Diseases, Karachi, Pakistan

    Syed Zahed Rasheed

  29. Red Crescent Institute of Cardiology, Hyderabad, Pakistan

    Fazal-ur-Rehman Memon

  30. Department of Medicine, Civil Hospital, Karachi, Pakistan

    Khalid Mehmood

  31. Department of Neurology, Liaquat National Hospital, Karachi, Pakistan

    Naveeduddin Ahmed

  32. Department of Medicine, Mayo Hospital and King Edward Medical University, Lahore, Pakistan

    Irshad Hussain Qureshi & Uzma Malik

  33. Department of Neurology, Lahore General Hospital, Lahore, Pakistan

    Tanveer-us-Salam & Wasim Iqbal

  34. All-India Institute of Medical Sciences, New Delhi, India

    Narinder Mehra

  35. Clinical and Medical Affairs, CardioDx, Inc., Redwood City, California, USA

    Jane Z Kuo

  36. Los Angeles Biomedical Research Institute and Department of Pediatrics, Institute for Translational Genomics and Population Sciences, Harbor-UCLA Medical Center, Torrance, California, USA

    Jane Z Kuo, Xiuqing Guo, Kent D Taylor, Jerome I Rotter & Yii-Der Ida Chen

  37. Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

    Wayne H-H Sheu & I-Te Lee

  38. School of Medicine, National Yang-Ming University, Taipei, Taiwan, and Chung Shan Medical University, Taichung, Taiwan

    Wayne H-H Sheu & I-Te Lee

  39. Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan

    Chao A Hsiung, Chih-Cheng Hsu & Ren-Hua Chung

  40. Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan

    Jyh-Ming J Juang & Tzung-Dau Wang

  41. Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

    Yi-Jen Hung

  42. Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan

    Wen-Jane Lee

  43. Hero DMC Heart Institute Ludhiana, Punjab, India

    Sarju Ralhan

  44. Genome Institute of Singapore, A*STAR, Singapore

    Yik Ying Teo

  45. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore

    Yik Ying Teo

  46. National University of Singapore Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore

    Yik Ying Teo

  47. Life Sciences Institute, National University of Singapore, Singapore

    Yik Ying Teo

  48. International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh

    Dewan S Alam

  49. MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC, USA

    Steve Epstein

  50. Copenhagen City Heart Study, Frederiksberg Hospital, Frederiksberg, Denmark

    Sune F Nielsen

  51. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

    Børge G Nordestgaard, Anne Tybjaerg-Hansen & Pia R Kamstrup

  52. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Børge G Nordestgaard

  53. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Anne Tybjaerg-Hansen & Ruth Frikke-Schmidt

  54. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands

    Marianne Benn & J Wouter Jukema

  55. Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands

    J Wouter Jukema

  56. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

    Naveed Sattar

  57. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands

    Roelof Smit

  58. Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan

    Kae-Woei Liang

  59. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

    Sonia Anand

  60. Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

    Dharambir K Sanghera

  61. Oklahoma Center for Neuroscience, Oklahoma City, Oklahoma, USA

    Dharambir K Sanghera

  62. National Institute for Health and Welfare, Helsinki, Finland

    Samuli Ripatti & Veikko Salomaa

  63. Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK

    Samuli Ripatti

  64. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    E Shyong Tai

  65. Cardiology Division, Department of Medicine and the Irving Institute for Clinical and Translational Research, Columbia University, New York, New York, USA

    Muredach Reilly

  66. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

    Guillaume Pare

  67. Department of Clinical Sciences, Hypertension and Cardiovascular Disease, Lund University, Malmö, Sweden

    Olle Melander

  68. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK

    John Danesh

  69. NIHR Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK

    John Danesh

  70. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Benjamin F Voight

  71. Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Benjamin F Voight

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  1. Wei Zhao
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  2. Asif Rasheed
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  3. Emmi Tikkanen
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  4. Jung-Jin Lee
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  14. Toshimasa Yamauch
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  15. John C Chambers
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  16. Peng Chen
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  17. Bishwa R Sapkota
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  18. Nabi Shah
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Contributions

A.R., B.F.V., B.G.N., D.J.R., D.S., D.S.A., J.I.R., M.R., O.M., P.F., R.C., R.J.F.L., S. Anand, S.E., S.M., S. Ripatti, T.-D.W., W.H.-H.S., and W. Zhao conceived of and designed the experiments. A.I., A.M., A.R., A.S.B., B.F.V., B.G.N., B.R.S., C.A.H., D.J.R., D.K.S., D.S., D.S.A., E.P.B., E.S.T., E.T., F.M., F.-u.-R.M., G.P., I.-T.L., I.H.Q., J.-J.L., J.C.C., J.I.R., J.M.M.H., J.S.K., J.W.J., J.Z.K., K.-W.L., K.D.T., K.M., K.T., M.B., N.M., M.O.-M., N.A., N.H.M., S.N.H.R., N.Q., N. Sattar, O.M., P.C., P.F., P.S., R.-H.C., R.C., R.F.-S., R.J.F.L., S. Abbas, S. Anand, S.E., S.J., S.M., S.N.H.R., S. Ralhan, S. Ripatti, S.Z.R., T.-D.W., T.-u.S., T.K., T.L.A., T.S., T.Y., U.M., W.H.-H.S., W.I., W. Zhang, W. Zhao, X.G., Y.-D.I.C., Y.-J.H., Y.L., Y.Y.T., and Z.Y. performed the experiments. A.R., A.S.B., B.F.V., C.A.H., D.S., E.D.A., E.P.B., E.T., I.-T.L., J.-J.L., J.-M.J.J., J.C.C., J.D., J.M.M.H., J.S.K., J.W.J., J.Z.K., K.-W.L., K.D.T., M.B., M.I., M.O.-M., M.R., N.K.M., N. Sattar, N. Shah, O.M., P.C., P.F., P.R.K., P.S., R.-H.C., R.C., R.F.-S., R.J.F.L., R.S., R.Y., S. Anand, S. Asma, S.D., S.F.N., S.M., S. Ralhan, T.-D.W., N.M., T.L.A., T.Q., T.S., T.Y., U.M., V.S., W.-J.L., W.H.-H.S., W. Zhang, W. Zhao, X.G., Y.-D.I.C., Y.-J.H., Y.L., and Y.Y.T. performed statistical analyses. A.I., A.R., A.S., A.S.B., A.T.-H., B.F.V., B.R.S., C.-C.H., C.A.H., D.K.S., D.S., E.D.A., E.P.B., E.S.T., E.T., F.M., G.P., I.-T.L., J.-J.L., J.-M.J.J., J.C.C., J.D., J.I.R., J.S.K., J.Z.K., K.-W.L., K.D.T., K.T., M.I., M.O.-M., M.R., N.H.M., N.Q., N. Sattar, N. Shah, O.M., P.C., P.R.K., P.S., R.-H.C., R.F.-S., R.J.F.L., R.S., R.Y., S. Abbas, S. Asma, S.D., S.J., S. Ralhan, T.K., T.L.A., T.Q., T.S., T.Y., U.M., V.S., W.-J.L., W. Zhao, X.G., Y.-D.I.C., Y.-J.H., Y.L., Y.Y.T., and Z.Y. analyzed the data. A.M., A.S., A.T.-H., B.F.V., B.G.N., D.J.R., D.S., F.u.R.M., G.P., I.H.Q., J.-M.J.J., J.D., J.W.J., N.M., K.M., M.B., M.R., N.A., P.R.K., R.S., S.E., S.N.H.R., S. Ripatti, S.Z.R., T.-u.-S., V.S., W.I., and W. Zhao contributed-reagents, materials, and/or analysis tools. A.R., A.S.B., B.F.V., D.J.R., D.K.S., D.S., E.T., G.P., J.-J.L., J.D., J.I.R., J.M.M.H., M.R., N. Sattar, V.S., and W. Zhao wrote the manuscript. D.S. and B.F.V. led the writing group. W. Zhao, A.R., E.T., B.F.V., and D.S. were equal contributors. B.F.V. and D.S. jointly supervised all aspects of the work.

Corresponding authors

Correspondence to Benjamin F Voight or Danish Saleheen.

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Competing interests

The authors declare competing financial interests from their affiliations with Pfizer, Regeneron Pharmaceuticals, Genenetech, and Eli Lilly.

Supplementary information

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Supplementary Note and Supplementary Figures 1–9. (PDF 4295 kb)

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Supplementary Tables 1–19

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Zhao, W., Rasheed, A., Tikkanen, E. et al. Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease. Nat Genet 49, 1450–1457 (2017). https://doi.org/10.1038/ng.3943

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