Letter | Published:

Association analyses based on false discovery rate implicate new loci for coronary artery disease

Nature Genetics volume 49, pages 13851391 (2017) | Download Citation

Abstract

Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10−8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; ncases = 10,801) as well as a stricter definition without angina (HARD; ncases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS2,3. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold2, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.

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Acknowledgements

This work was funded by British Heart Foundation (BHF) grants RG/14/5/30893 to P.D. and FS/14/66/31293 to O.G. The work of P.D. forms part of the research themes contributing to the translational research portfolios of the Barts Biomedical Research Centre and Leicester Biomedical Research Centre funded by the UK National Institute for Health Research (NIHR). F.Y.L. and S.E.H. are funded by NIHR. C.P.N., T.R.W. and N.J.S. are funded from BHF, the Transatlantic Networks of Excellence Award (12CVD02) from the Leducq Foundation and EU-FP7/2007-2013 grant HEALTH-F2-2013-601456. N.J.S. is an NIHR Senior Investigator. PROCARDIS was supported by EU-FP6 (LSHM-CT- 2007-037273), AstraZeneca, BHF, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Söderberg Foundation, Karolinska Institutet, Foundation Strategic Research and the Stockholm County Council (560283). M.F. and H.W. are supported by Wellcome Trust award 090532/Z/09/Z, and M.F., H.W. and T.K. are supported by the BHF Centre of Research Excellence. A.G., H.W. and T.K. are supported by FP7/2007-2013 (HEALTH-F2-2013-601456 (CVGenes@Target)), and A.G. is supported by the Wellcome Trust and the TriPartite Immunometabolism Consortium-Novo Nordisk Foundation (NNF15CC0018486). HPS (ISRCTN48489393) was supported by the Medical Research Council (MRC), BHF, Merck and Co, and Roche Vitamins, Ltd. HPS acknowledges National Blood Service donor and UK-Twin Study controls (Wellcome Trust 07611, FP7/2007-2013). J.C.H. is funded by BHF (FS/14/55/30806). The Mount Sinai BioMe Biobank is supported by the Andrea and Charles Bronfman Philanthropies. The GLACIER Study and P.W.F. are funded by the European Commission (CoG-2015_681742_NASCENT), the Swedish Research Council (Distinguished Young Researchers Award), the Heart-Lung Foundation and the Novo Nordisk Foundation. OHGS studies were funded by the Canadian Institutes of Health Research, the Canada Foundation for Innovation and the Heart & Stroke Foundation of Canada. LURIC was funded from the EU-FP7 (Atheroremo (201668), RiskyCAD (305739), INTERREG IV Oberrhein Program), the European Regional Development Fund (ERDF), Wissenschaftsoffensive TMO and from the German Ministry for Education and Research, project e:AtheroSysMed (01ZX1313A-K). LOLIPOP is supported by the NIHR-BRC Imperial College Healthcare NHS Trust, BHF (SP/04/002), MRC (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z), NIHR (RP-PG-0407-10371), EU-FP7 (EpiMigrant, 279143) and Action on Hearing Loss (G51). The Helsinki Sudden Death Study was funded by EU-FP7 (201668, AtheroRemo), the Tampere University Foundation, Tampere University Hospital Medical Funds (grants 9M048 and 9N035 for T.L.), the Emil Aaltonen Foundation (T.L.), the Finnish Foundation of Cardiovascular Research (T.L., P.K.), the Pirkanmaa Regional Fund of the Finnish Cultural Foundation, the Yrjö Jahnsson Foundation, the Tampere Tuberculosis Foundation (T.L.), the Signe and Ane Gyllenberg Foundation (T.L.) and the Diabetes Research Foundation of the Finnish Diabetes Association (T.L.). M.T. (PG/16/49/32176) and R.C. (FS/12/80/29821) are supported by BHF. E.Z. acknowledges Wellcome Trust funding (098051). H.S. was supported by Deutsche Forschungsgemeinschaft (Sonderforschungsbereich CRC 1123 (B02)). The MRC/BHF Cardiovascular Epidemiology Unit was funded by MRC (G0800270), BHF (SP/09/002), NIHR-BRC Cambridge, the European Research Council (ERC; 268834), EU-FP7 (HEALTH-F2-2012-279233), Pfizer, Merck and Biogen. EPIC-CVD was supported by the University of Cambridge, EU-FP7 (HEALTH-F2-2012-279233), MRC (G0800270), BHF (SP/09/002) and ERC (268834). We thank all EPIC participants and staff and S. Spackman. EGCUT was funded by the Estonian Research Council grant for data management and the EPIC-CVD Coordinating Centre team. (IUT20-60), the Centre of Excellence in Genomics and Translational Medicine (GENTRANSMED), EU structural fund (Archimedes Foundation; 3.2.1001.11-0033), PerMed I and EU2020 (692145 ePerMed). This research was supported by BHF (SP/13/2/30111) and conducted using the UK Biobank Resource (application number 9922).

Author information

Author notes

    • Christopher P Nelson
    • , Anuj Goel
    • , Adam S Butterworth
    • , Stavroula Kanoni
    • , Heribert Schunkert
    • , Martin Farrall
    • , John Danesh
    • , Nilesh J Samani
    • , Hugh Watkins
    •  & Panos Deloukas

    These authors contributed equally to this work.

Affiliations

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

    • Christopher P Nelson
    • , Tom R Webb
    • , Florence Y Lai
    • , Stephen E Hamby
    •  & Nilesh J Samani
  2. National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK.

    • Christopher P Nelson
    • , Tom R Webb
    • , Florence Y Lai
    • , Stephen E Hamby
    •  & Nilesh J Samani
  3. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

    • Anuj Goel
    • , Christopher Grace
    • , Theodosios Kyriakou
    • , Martin Farrall
    •  & Hugh Watkins
  4. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Anuj Goel
    • , Christopher Grace
    • , Theodosios Kyriakou
    • , Martin Farrall
    •  & Hugh Watkins
  5. MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Adam S Butterworth
    • , Tao Jiang
    • , Emanuele Di Angelantonio
    • , Joanna M M Howson
    • , Michael J Sweeting
    •  & John Danesh
  6. NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Adam S Butterworth
    • , Emanuele Di Angelantonio
    •  & John Danesh
  7. William Harvey Research Institute, Barts & the London Medical School, Queen Mary University of London, London, UK.

    • Stavroula Kanoni
    • , Eirini Marouli
    • , Ioanna Ntalla
    • , Olga Giannakopoulou
    •  & Panos Deloukas
  8. Centre for Genomic Health, Queen Mary University of London, London, UK.

    • Stavroula Kanoni
    • , Eirini Marouli
    • , Ioanna Ntalla
    • , Olga Giannakopoulou
    •  & Panos Deloukas
  9. German Heart Center Munich, Clinic at Technische Universität München and Deutsches Zentrum für Herz- und Kreislauferkrankungen (DZHK), partner site Munich Heart Alliance, Munich, Germany.

    • Lingyao Zeng
    • , Adnan Kastrati
    • , Thorsten Kessler
    •  & Heribert Schunkert
  10. CTSU, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

    • Jemma C Hopewell
    •  & Robert Clarke
  11. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

    • Themistocles L Assimes
  12. Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Erwin P Bottinger
    • , Yingchang Lu
    •  & Ruth J F Loos
  13. Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

    • John C Chambers
    • , Evangelos Evangelou
    •  & Ioanna Tzoulaki
  14. Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Southall, UK.

    • John C Chambers
    •  & Jaspal S Kooner
  15. Imperial College Healthcare NHS Trust, London, UK.

    • John C Chambers
    •  & Jaspal S Kooner
  16. Molecular and Clinical Medicine, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.

    • Colin N A Palmer
  17. Pharmacogenomics Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.

    • Colin N A Palmer
  18. Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

    • Richard M Cubbon
  19. Cardiac Arrhythmia Service and Cardiovascular Research Center, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, Massachusetts, USA.

    • Patrick Ellinor
  20. Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia.

    • Raili Ermel
    •  & Arno Ruusalepp
  21. Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.

    • Evangelos Evangelou
    •  & Ioanna Tzoulaki
  22. Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Lund University, Malmö, Sweden.

    • Paul W Franks
  23. Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.

    • Paul W Franks
  24. Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå, Sweden.

    • Paul W Franks
  25. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Dongfeng Gu
  26. Institute of Cardiovascular Science, University College London,London, UK.

    • Aroon D Hingorani
    •  & Amand F Schmidt
  27. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.

    • Erik Ingelsson
    •  & Xiangfeng Lu
  28. Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.

    • Terho Lehtimäki
  29. Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Yingchang Lu
  30. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.

    • Winfried März
  31. Medical Clinic V (Nephrology, Rheumatology, Hypertensiology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

    • Winfried März
  32. Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.

    • Winfried März
  33. Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

    • Ruth McPherson
  34. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Andres Metspalu
  35. Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK.

    • Mar Pujades-Rodriguez
  36. Clinical Gene Networks AB, Stockholm, Sweden.

    • Arno Ruusalepp
    •  & Johan L M Björkegren
  37. Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Eric E Schadt
    •  & Johan L M Björkegren
  38. Lebanese American University, School of Medicine, Beirut, Lebanon.

    • Pierre A Zalloua
  39. Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Pierre A Zalloua
  40. Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.

    • Kamal AlGhalayini
  41. Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

    • Bernard D Keavney
  42. Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

    • Bernard D Keavney
    •  & Maciej Tomaszewski
  43. Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK.

    • Jaspal S Kooner
  44. Mindich Child Health Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ruth J F Loos
  45. Farr Institute of Health Informatics, UCL, London, UK.

    • Riyaz S Patel
  46. Bart's Heart Centre, St Bartholomew's Hospital, London, UK.

    • Riyaz S Patel
  47. Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

    • Martin K Rutter
  48. Manchester Diabetes Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

    • Martin K Rutter
  49. Division of Medicine, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

    • Maciej Tomaszewski
  50. Wellcome Trust Sanger Institute, Hinxton, UK.

    • Eleftheria Zeggini
  51. Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.

    • Jeanette Erdmann
  52. DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany.

    • Jeanette Erdmann
  53. University Heart Center Lübeck, Lübeck, Germany.

    • Jeanette Erdmann
  54. Department of Nutrition-Dietetics, Harokopio University, Athens, Greece.

    • George Dedoussis
  55. Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden.

    • Johan L M Björkegren
  56. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • John Danesh
  57. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.

    • Panos Deloukas

Consortia

  1. EPIC-CVD Consortium

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

  2. CARDIoGRAMplusC4D

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

  3. The UK Biobank CardioMetabolic Consortium CHD working group

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

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Contributions

C.P.N., A.G., A.S.B., S.K., T.R.W., E.M., I.N., J.C.H., O.G., H.S., M.F., J.D., N.J.S., H.W. and P.D. wrote and edited the manuscript. All authors contributed and discussed the results and commented on the manuscript. A.S.B., O.G., T.J., L.Z., S.E.H., E.A., T.L.A., E.P.B., J.C.C., R.C., R.M.C., P.E., R.E., E.E., P.W.F., C.G., D.G., A.H., J.M.M.H., E.I., A.K., T. Kessler, T. Kyriakou, T.L., X.L., Y.L., W.M., R.M., A.M., C.N.A.P., M.P.-R., A.F.S., M.J.S., P.A.Z., K.A., R.J.F.L., E.Z., J.E., G.D., H.S., J.D., N.J.S., H.W. and P.D. generated data and cohorts. C.P.N., A.S.B., I.N., F.Y.L., J.C.H., O.G., B.D.K., J.S.K., R.J.F.L., R.S.P., M.R., M.T., I.T., E.Z., J.E., G.D., H.S., J.D., N.J.S., H.W. and P.D. analyzed phenotype data for UKBB and replication studies. C.P.N., A.G., A.S.B., S.K., T.J. and M.F. performed the statistical analyses. C.P.N., S.K., T.R.W., A.S.B., R.E., A.R., E.E.S. and J.L.M.B. performed functional annotation. E.M. and P.D. performed biological and clinical enrichment and pathway analyses.

Competing interests

P.W.F. has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative (IMI) project. E.I. is an advisor and consultant for Precision Wellness, Inc., and an advisor for Cellink for work unrelated to the present project. M.K.R. has acted as a consultant for GSK, Roche, Ascensia and MSD and participated in advisory board meetings on their behalf. M.K.R. has received lecture fees from MSD and grant support from Novo Nordisk, MSD and GSK. J.L.M.B. is the founder and chairman of Clinical Gene Networks. CGN has financially contributed to the STARNET study. J.L.M.B., E.E.S. and A.R. are on the board of directors for CGN. J.L.M.B. and A.R. own equity in CGN and receive financial compensation from CGN.

Corresponding author

Correspondence to Hugh Watkins.

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–10, Supplementary Tables 1, 3, 5, 8, 12 and 13, and Supplementary Note.

  2. 2.

    Life Sciences Reporting Summary

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    Supplementary Tables 2, 4, 6, 7 and 9–11

    Supplementary Tables 2, 4, 6, 7 and 9–11.

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DOI

https://doi.org/10.1038/ng.3913

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