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Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Nature Genetics volume 49, pages 1113–1119 (2017)Cite this article

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Abstract

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide1,2. Although 58 genomic regions have been associated with CAD thus far3,4,5,6,7,8,9, most of the heritability is unexplained9, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP–CAD associations (P < 5 × 10−8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

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Figure 1: Schematic of the study design.
Figure 2: Plot showing the association of ∼79,000 variants with CAD (−log10P) in up to 88,192 cases and 162,544 controls from the all-ancestry fixed-effects meta-analysis.

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Acknowledgements

J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator and NIHR Senior Investigator. J.D.E. and A.D.J. were supported by NHLBI Intramural Research Program funds. N.F. is supported by R21HL123677-01 and R56 DK104806-01A1. N.S. is supported by the British Heart Foundation and is an NIHR Senior Investigator. T.L.A. is supported by NIH career development award K23DK088942. This work was funded by the UK Medical Research Council (G0800270), the British Heart Foundation (SP/09/002), the UK National Institute for Health Research Cambridge Biomedical Research Centre, the European Research Council (268834), European Commission Framework Programme 7 (HEALTH-F2-2012-279233) and Pfizer. The eQTL database construction was supported by NHLBI intramural funds. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the US Department of Health and Human Services.

A full list of acknowledgments for the studies contributing to this work is provided in the Supplementary Note.

Author information

Author notes

  1. Wei Zhao, Daniel R Barnes, Themistocles L Assimes, John Danesh, Adam S Butterworth and Danish Saleheen: These authors contributed equally to this work.

Authors and Affiliations

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

    Joanna M M Howson, Daniel R Barnes, Weang-Kee Ho, Robin Young, Dirk S Paul, Daniel F Freitag, Benjamin B Sun, Wei-Yu Lin, Praveen Surendran, Emanuele Di Angelantonio, Rajiv Chowdhury, John Danesh, Adam S Butterworth & Danish Saleheen

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

    Wei Zhao & Danish Saleheen

  3. Department of Applied Mathematics, University of Nottingham Malaysia Campus, Semenyih, Malaysia

    Weang-Kee Ho

  4. Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK

    Robin Young

  5. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA

    Lindsay L Waite & Devin Absher

  6. Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA

    Eric B Fauman

  7. Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, California, USA

    Elias L Salfati, Thomas Quertermous & Themistocles L Assimes

  8. Stanford Cardiovascular Institute, Stanford University, Stanford, California, USA

    Elias L Salfati, Thomas Quertermous & Themistocles L Assimes

  9. National Heart, Lung, and Blood Institute, Population Sciences Branch, Bethesda, Maryland, USA

    John D Eicher & Andrew D Johnson

  10. NHLBI and Boston University's The Framingham Heart Study, Framingham, Massachusetts, USA

    John D Eicher & Andrew D Johnson

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

    Wayne H H Sheu

  12. School of Medicine, National Yang-Ming University, Taipei, Taiwan

    Wayne H H Sheu

  13. College of Medicine, National Defense Medical Center, Taipei, Taiwan

    Wayne H H Sheu & Yi-Jen Hung

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

    Sune F Nielsen, Katrine L Rasmussen, Pia R Kamstrup & Børge G Nordestgaard

  15. Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK

    Wei-Yu Lin

  16. Pfizer Worldwide Research and Development, Stockholm, Sweden

    Anders Malarstig

  17. Pfizer Worldwide Research and Development, Human Genetics, Cambridge, Massachusetts, USA

    Jemma B Wilk

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

    Anne Tybjærg-Hansen

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

    Anne Tybjærg-Hansen & Børge G Nordestgaard

  20. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Panos Deloukas

  21. Centre for Genomic Health, Queen Mary University of London, London, UK

    Panos Deloukas

  22. Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany

    Jeanette Erdmann

  23. DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany

    Jeanette Erdmann

  24. University Heart Center Lübeck, Lübeck, Germany

    Jeanette Erdmann

  25. Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

    Sekar Kathiresan

  26. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

    Sekar Kathiresan

  27. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK

    Nilesh J Samani

  28. NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK

    Nilesh J Samani

  29. Deutsches Herzzentrum München, Technische Universität München, Munich, Germany

    Heribert Schunkert

  30. DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany

    Heribert Schunkert

  31. Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    Hugh Watkins

  32. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Hugh Watkins

  33. Department of Genetics and Genomic Sciences, Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Ron Do

  34. Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Daniel J Rader

  35. University of Florida College of Pharmacy, Gainesville, Florida, USA

    Julie A Johnson

  36. Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, Ohio, USA

    Stanley L Hazen

  37. Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA

    Arshed A Quyyumi

  38. Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA

    John A Spertus

  39. Department of Biomedical and Health Informatics, University of Missouri–Kansas City, Kansas City, Missouri, USA

    John A Spertus

  40. College of Medicine, University of Florida, Gainesville, Florida, USA

    Carl J Pepine

  41. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA

    Nora Franceschini, Anne Justice, Kari E North, Kristin Young & Mariaelisa Graff

  42. Department of Epidemiology, University of Washington, Seattle, Washington, USA

    Alex P Reiner

  43. Department of Statistics and Biostatistics, Rutgers University, Piscataway, New Jersey, USA

    Steven Buyske

  44. Division of Genomic Medicine, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA

    Lucia A Hindorff

  45. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Cara L Carty, Charles Kooperberg & Ulrike Peters

  46. Carolina Center for Genome Sciences, Chapel Hill, North Carolina, USA

    Kari E North

  47. Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA

    Eric Boerwinkle

  48. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA

    Eric Boerwinkle

  49. Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan

    Chao A Hsiung, Ying-Hsiang Chen & Ren-Hua Chung

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

    Wen-Jane Lee

  51. Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA

    Kent D Taylor, Xiuqing Guo & Yii-Der Ida Chen

  52. School of Medicine, Chung Shan Medical University, Taichung, Taiwan

    I-Te Lee

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

    Yi-Jen Hung

  54. Departments of Pediatrics and Medicine, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA

    Jerome I Rotter

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

    Jyh-Ming J Juang & Tzung-Dau Wang

  56. National Taiwan University College of Medicine, Taipei, Taiwan

    Jyh-Ming J Juang & Tzung-Dau Wang

  57. Centre for Non-Communicable Disease, Karachi, Pakistan

    Asif Rasheed, Philippe Frossard & Danish Saleheen

  58. School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada

    Dewan S Alam

  59. National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Bangladesh

    Abdulla al Shafi Majumder

  60. National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK

    Emanuele Di Angelantonio, John Danesh & Adam S Butterworth

  61. Wellcome Trust Sanger Institute, Hinxton, UK

    John Danesh

  62. Department of Medicine, British Heart Foundation Cambridge Centre of Excellence, University of Cambridge, Cambridge, UK

    John Danesh

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Consortia

CARDIoGRAMplusC4D

EPIC-CVD

Contributions

Central analysis group: J.M.M.H., W.Z., D.R.B., T.L.A., A.S.B., D.S. Writing group: J.M.M.H., W.Z., D.R.B., D.S.P., T.L.A., A.S.B., J.D. Study analysts: J.M.M.H., W.-K.H., R.Y., L.L.W., E.L.S., S.F.N., W.-Y.L., R.D., N.F., A.J., A.P.R., C.L.C., K.Y., M.G., D.A., C.A.H., Y.-H.C., X.G., T.L.A. Study PIs and co-PIs: W.H.-H.S., P.D., J.E., S.K., N.J.S., H.S., H.W., D.J.R., J.A.J., S.L.H., A.A.Q., J.S., C.J.P., K.E.N., C.K., U.P., C.A.H., W.-J.L., I.-T.L., R.-H.C., Y.-J.H., J.I.R., J.-M.J.J., T.Q., T.-D.W., D.S.A., A.a.S.M., E.D.A., R.C., Y.-D.I.C., B.G.N., T.L.A., J.D., A.S.B., D.S., A.R., P.F. Bioinformatics, eQTL, pQTL and pathway analyses: D.S.P., W.Z., D.R.B., D.F.F., T.L.A., E.B.F., A.M., J.B.W., E.L.S., B.B.S., A.S.B., J.D.E., A.D.J., P.S., T.L.A., J.M.M.H. Genotyping: S.B., L.A.H., C.K., E.B., U.P., D.A., K.D.T., T.Q., T.L.A. Phenotyping: W.H.H.S., A.T.-H., K.L.R., P.R.K., K.E.N., C.K., C.A.H., W.-J.L., I.-T.L., R.-H.C., Y.-J.H., J.-M.J.J., T.Q., Y.-D.I.C.

Corresponding author

Correspondence to Joanna M M Howson.

Ethics declarations

Competing interests

A.M., E.B.F. and J.B.W. are full-time employees of Pfizer. D.F.F. is now a full-time employee of Bayer AG, Germany. J.D. reports personal fees and non-financial support from Merck Sharp & Dohme UK Atherosclerosis, the Novartis Cardiovascular & Metabolic Advisory Board, the Pfizer Population Research Advisory Panel and the Sanofi Advisory Board.

Additional information

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8, Supplementary Tables 1–4, 6 and 7, and Supplementary Note (PDF 7944 kb)

Supplementary Table 5

Results of meta-analyses across the studies (including all samples) with de novo genotyping at the new CAD-associated SNPs reported in Supplementary Table 4. (XLSX 17 kb)

Supplementary Table 8

Ingenuity Pathway Analysis results. (XLSX 19 kb)

Supplementary Table 9

Coordinates for the genomics regions used for each new CAD locus. (XLSX 9 kb)

Supplementary Table 10

eQTL lookups of the 15 new CAD-associated regions. (XLSX 16 kb)

Supplementary Table 11

HaploReg enrichment analyses of H3K27ac enhancer marks. (XLSX 9 kb)

Supplementary Table 12

Association results for established CAD loci. (XLSX 30 kb)

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Howson, J., Zhao, W., Barnes, D. et al. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. Nat Genet 49, 1113–1119 (2017). https://doi.org/10.1038/ng.3874

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