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

Affiliations

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

Authors

Affiliations

Abstract

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

Molecular Biology Databases

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