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

doi:10.1038/ng.3913

. 2017 Sep;49(9):1385-1391.

doi: 10.1038/ng.3913. Epub 2017 Jul 17.

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

Christopher P Nelson^{1

2}, Anuj Goel^{3

4}, Adam S Butterworth^{5

6}, Stavroula Kanoni^{7

8}, Tom R Webb^{1

2}, Eirini Marouli^{7

8}, Lingyao Zeng⁹, Ioanna Ntalla^{7

8}, Florence Y Lai^{1

2}, Jemma C Hopewell¹⁰, Olga Giannakopoulou^{7

8}, Tao Jiang⁵, Stephen E Hamby^{1

2}, Emanuele Di Angelantonio^{5

6}, Themistocles L Assimes¹¹, Erwin P Bottinger¹², John C Chambers^{13

14

15}, Robert Clarke¹⁰, Colin N A Palmer^{16

17}, Richard M Cubbon¹⁸, Patrick Ellinor¹⁹, Raili Ermel²⁰, Evangelos Evangelou^{13

21}, Paul W Franks^{22

23

24}, Christopher Grace^{3

4}, Dongfeng Gu²⁵, Aroon D Hingorani²⁶, Joanna M M Howson⁵, Erik Ingelsson²⁷, Adnan Kastrati⁹, Thorsten Kessler⁹, Theodosios Kyriakou^{3

4}, Terho Lehtimäki²⁸, Xiangfeng Lu²⁷, Yingchang Lu^{12

29}, Winfried März^{30

31

32}, Ruth McPherson³³, Andres Metspalu³⁴, Mar Pujades-Rodriguez³⁵, Arno Ruusalepp^{20

36}, Eric E Schadt³⁷, Amand F Schmidt²⁶, Michael J Sweeting⁵, Pierre A Zalloua^{38

39}, Kamal AlGhalayini⁴⁰, Bernard D Keavney^{41

42}, Jaspal S Kooner^{14

15

43}, Ruth J F Loos^{12

44}, Riyaz S Patel^{45

46}, Martin K Rutter^{47

48}, Maciej Tomaszewski^{42

49}, Ioanna Tzoulaki^{13

21}, Eleftheria Zeggini⁵⁰, Jeanette Erdmann^{51

52

53}, George Dedoussis⁵⁴, Johan L M Björkegren^{36

37

55}; EPIC-CVD Consortium; CARDIoGRAMplusC4D; UK Biobank CardioMetabolic Consortium CHD working group; Heribert Schunkert⁹, Martin Farrall^{3

4}, John Danesh^{5

6

56}, Nilesh J Samani^{1

2}, Hugh Watkins^{3

4}, Panos Deloukas^{7

8

57}

Affiliations

¹ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
² National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK.
³ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁴ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁵ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁷ William Harvey Research Institute, Barts &the London Medical School, Queen Mary University of London, London, UK.
⁸ Centre for Genomic Health, Queen Mary University of London, London, UK.
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.
¹⁰ CTSU, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹¹ Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
¹² Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹³ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
¹⁴ Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Southall, UK.
¹⁵ Imperial College Healthcare NHS Trust, London, UK.
¹⁶ Molecular and Clinical Medicine, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.
¹⁷ Pharmacogenomics Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.
¹⁸ Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.
¹⁹ Cardiac Arrhythmia Service and Cardiovascular Research Center, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, Massachusetts, USA.
²⁰ Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia.
²¹ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
²² Department of Clinical Sciences, Genetic &Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Lund University, Malmö, Sweden.
²³ Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
²⁴ Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå, Sweden.
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.
²⁶ Institute of Cardiovascular Science, University College London,London, UK.
²⁷ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
²⁸ Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
²⁹ Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
³⁰ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
³¹ Medical Clinic V (Nephrology, Rheumatology, Hypertensiology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
³² Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.
³³ Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
³⁴ Estonian Genome Center, University of Tartu, Tartu, Estonia.
³⁵ Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK.
³⁶ Clinical Gene Networks AB, Stockholm, Sweden.
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.
³⁸ Lebanese American University, School of Medicine, Beirut, Lebanon.
³⁹ Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁴⁰ Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
⁴¹ Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
⁴² Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁴³ Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK.
⁴⁴ Mindich Child Health Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁴⁵ Farr Institute of Health Informatics, UCL, London, UK.
⁴⁶ Bart's Heart Centre, St Bartholomew's Hospital, London, UK.
⁴⁷ Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
⁴⁸ Manchester Diabetes Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁴⁹ Division of Medicine, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁵⁰ Wellcome Trust Sanger Institute, Hinxton, UK.
⁵¹ Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.
⁵² DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany.
⁵³ University Heart Center Lübeck, Lübeck, Germany.
⁵⁴ Department of Nutrition-Dietetics, Harokopio University, Athens, Greece.
⁵⁵ Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden.
⁵⁶ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
⁵⁷ Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.

PMID: 28714975
DOI: 10.1038/ng.3913

Free article

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

Christopher P Nelson et al. Nat Genet. 2017 Sep.

Free article

. 2017 Sep;49(9):1385-1391.

doi: 10.1038/ng.3913. Epub 2017 Jul 17.

Authors

Affiliations

¹ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
² National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK.
³ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁴ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁵ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁷ William Harvey Research Institute, Barts &the London Medical School, Queen Mary University of London, London, UK.
⁸ Centre for Genomic Health, Queen Mary University of London, London, UK.
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.
¹⁰ CTSU, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹¹ Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
¹² Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹³ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
¹⁴ Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Southall, UK.
¹⁵ Imperial College Healthcare NHS Trust, London, UK.
¹⁶ Molecular and Clinical Medicine, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.
¹⁷ Pharmacogenomics Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.
¹⁸ Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.
¹⁹ Cardiac Arrhythmia Service and Cardiovascular Research Center, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, Massachusetts, USA.
²⁰ Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia.
²¹ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
²² Department of Clinical Sciences, Genetic &Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Lund University, Malmö, Sweden.
²³ Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
²⁴ Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå, Sweden.
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.
²⁶ Institute of Cardiovascular Science, University College London,London, UK.
²⁷ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
²⁸ Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
²⁹ Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
³⁰ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
³¹ Medical Clinic V (Nephrology, Rheumatology, Hypertensiology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
³² Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.
³³ Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
³⁴ Estonian Genome Center, University of Tartu, Tartu, Estonia.
³⁵ Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK.
³⁶ Clinical Gene Networks AB, Stockholm, Sweden.
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.
³⁸ Lebanese American University, School of Medicine, Beirut, Lebanon.
³⁹ Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁴⁰ Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
⁴¹ Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
⁴² Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁴³ Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK.
⁴⁴ Mindich Child Health Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁴⁵ Farr Institute of Health Informatics, UCL, London, UK.
⁴⁶ Bart's Heart Centre, St Bartholomew's Hospital, London, UK.
⁴⁷ Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
⁴⁸ Manchester Diabetes Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁴⁹ Division of Medicine, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁵⁰ Wellcome Trust Sanger Institute, Hinxton, UK.
⁵¹ Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.
⁵² DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany.
⁵³ University Heart Center Lübeck, Lübeck, Germany.
⁵⁴ Department of Nutrition-Dietetics, Harokopio University, Athens, Greece.
⁵⁵ Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden.
⁵⁶ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
⁵⁷ Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.

PMID: 28714975
DOI: 10.1038/ng.3913

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; n_cases = 10,801) as well as a stricter definition without angina (HARD; n_cases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, 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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References

1. Nat Genet. 2016 Sep;48(9):980-3 - PubMed
1. Nat Commun. 2015 Jan 19;6:5890 - PubMed
1. Eur J Epidemiol. 2007;22(2):129-41 - PubMed
1. Bioinformatics. 2016 Oct 15;32(20):3207-3209 - PubMed
1. Nucleic Acids Res. 2012 Jan;40(Database issue):D930-4 - PubMed

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[1] Nat Genet. 2016 Sep;48(9):980-3 - PubMed

[2] Nat Genet. 2016 Sep;48(9):980-3 - PubMed

[3] Nat Commun. 2015 Jan 19;6:5890 - PubMed

[4] Nat Commun. 2015 Jan 19;6:5890 - PubMed

[5] Eur J Epidemiol. 2007;22(2):129-41 - PubMed

[6] Eur J Epidemiol. 2007;22(2):129-41 - PubMed

[7] Bioinformatics. 2016 Oct 15;32(20):3207-3209 - PubMed

[8] Bioinformatics. 2016 Oct 15;32(20):3207-3209 - PubMed

[9] Nucleic Acids Res. 2012 Jan;40(Database issue):D930-4 - PubMed

[10] Nucleic Acids Res. 2012 Jan;40(Database issue):D930-4 - PubMed

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

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

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