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Nat Genet. 2015 Oct;47(10):1121-1130. doi: 10.1038/ng.3396. Epub 2015 Sep 7.

A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.

Nikpay M#1, Goel A#2,3, Won HH#4,5,6,7, Hall LM#8, Willenborg C#9,10, Kanoni S#11, Saleheen D#12,13, Kyriakou T2,3, Nelson CP8,14, Hopewell JC15, Webb TR8,14, Zeng L16,17, Dehghan A18, Alver M19,20, Armasu SM21, Auro K22,23,24, Bjonnes A4,6, Chasman DI25,26, Chen S27, Ford I28, Franceschini N29, Gieger C17,30,31, Grace C2,3, Gustafsson S32,33, Huang J34, Hwang SJ35,36, Kim YK37, Kleber ME38, Lau KW15, Lu X27, Lu Y39,40, Lyytikäinen LP41,42, Mihailov E19, Morrison AC43, Pervjakova N19,22,23,24, Qu L44, Rose LM25, Salfati E45, Saxena R4,6,46, Scholz M47,48, Smith AV49,50, Tikkanen E51,52, Uitterlinden A18, Yang X27, Zhang W53,54, Zhao W12, de Andrade M21, de Vries PS18, van Zuydam NR3,55, Anand SS56, Bertram L57,58, Beutner F48,59, Dedoussis G60, Frossard P13, Gauguier D61, Goodall AH14,62, Gottesman O39, Haber M63, Han BG37, Huang J64, Jalilzadeh S2,3, Kessler T16,65, König IR10,66, Lannfelt L67, Lieb W68, Lind L69, Lindgren CM3,4, Lokki ML70, Magnusson PK71, Mallick NH72, Mehra N73, Meitinger T17,74,75, Memon FU76, Morris AP3,77, Nieminen MS78, Pedersen NL71, Peters A17,30, Rallidis LS79, Rasheed A13,76, Samuel M13, Shah SH80, Sinisalo J78, Stirrups KE11,81, Trompet S82,83, Wang L27,84, Zaman KS85, Ardissino D86,87, Boerwinkle E43,88, Borecki IB89, Bottinger EP39, Buring JE25, Chambers JC53,54,90, Collins R15, Cupples LA35,36, Danesh J34,91, Demuth I92,93, Elosua R94, Epstein SE95, Esko T4,19,96,97, Feitosa MF89, Franco OH18, Franzosi MG98, Granger CB80, Gu D27, Gudnason V49,50, Hall AS99, Hamsten A100, Harris TB101, Hazen SL102, Hengstenberg C16,17, Hofman A18, Ingelsson E3,32,33,103, Iribarren C104, Jukema JW82,105,106, Karhunen PJ41,107, Kim BJ37, Kooner JS54,90,108, Kullo IJ109, Lehtimäki T41,42, Loos RJF39,40,110, Melander O111, Metspalu A19,20, März W38,112,113, Palmer CN55, Perola M19,22,23,24, Quertermous T45,114, Rader DJ115,116, Ridker PM25,26, Ripatti S34,51,52, Roberts R117, Salomaa V118, Sanghera DK119,120,121, Schwartz SM122,123, Seedorf U124, Stewart AF1, Stott DJ125, Thiery J48,126, Zalloua PA63,127, O'Donnell CJ35,128,129, Reilly MP116, Assimes TL45,114, Thompson JR130, Erdmann J9,10, Clarke R15, Watkins H2,3, Kathiresan S4,5,6,7, McPherson R1, Deloukas P11,131, Schunkert H16,17, Samani NJ8,14, Farrall M2,3.

Author information

1
Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada.
2
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
3
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
4
Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.
5
Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
6
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
7
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
8
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
9
Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany.
10
DZHK (German Research Center for Cardiovascular Research) partner site Hamburg-Lübeck-Kiel, Lübeck, Germany.
11
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
12
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
13
Center for Non-Communicable Diseases, Karachi, Pakistan.
14
NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
15
CTSU, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
16
Deutsches Herzzentrum München, Technische Universität München, München, Germany.
17
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, München, Germany.
18
Department of Epidemiology, Erasmus University Medical center, Rotterdam, The Netherlands.
19
Estonian Genome Center, University of Tartu, Tartu, Estonia.
20
Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
21
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
22
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
23
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
24
Diabetes & Obesity Research Program, University of Helsinki, Helsinki, Finland.
25
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
26
Harvard Medical School, Boston, Massachusetts, USA.
27
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.
28
Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
29
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.
30
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
31
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
32
Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
33
Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
34
Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
35
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.
36
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
37
Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, Korea.
38
Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany.
39
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, USA.
40
The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York, USA.
41
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
42
Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
43
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
44
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
45
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, California, USA.
46
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
47
Institute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, Leipzig, Germany.
48
LIFE Research Center of Civilization Diseases, Leipzig, Germany.
49
Icelandic Heart Association, Kopavogur, Iceland.
50
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
51
Department of Public Health, University of Helsinki, Helsinki, Finland.
52
Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
53
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
54
Department of Cardiology, Ealing Hospital NHS Trust, Middlesex, UK.
55
Medical Research Institute, University of Dundee, Dundee, UK.
56
Population Health Research Institute, Hamilton Health Sciences, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
57
Platform for Genome Analytics, Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
58
Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology, and Medicine, London, UK.
59
Heart Center Leipzig, Cardiology, University of Leipzig, Leipzig, Germany.
60
Department of Dietetics-Nutrition, Harokopio University, Athens, Greece.
61
INSERM, UMRS1138, Centre de Recherche des Cordeliers, Paris, France.
62
Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK.
63
Lebanese American University, School of Medicine, Beirut, Lebanon.
64
Hypertension Division, Fuwai Hospital, National Center For Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
65
Klinikum rechts der Isar, München, Germany.
66
Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany.
67
Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
68
Institut für Epidemiologie, Christian-Albrechts Universität zu Kiel, Kiel, Germany.
69
Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
70
Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
71
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
72
Punjab Institute of Cardiology, Lahore, Pakistan.
73
All India Institute of Medical Sciences, New Delhi, India.
74
Institut für Humangenetik, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
75
Institute of Human Genetics, Technische Universität München, München, Germany.
76
Red Crescent Institute of Cardiology, Hyderabad, Pakistan.
77
Department of Biostatistics, University of Liverpool, Liverpool, UK.
78
Department of Medicine, Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
79
Second Department of Cardiology, Attikon Hospital, School of Medicine, University of Athens, Athens, Greece.
80
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
81
Department of Haematology, University of Cambridge, Cambridge, UK.
82
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
83
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
84
National Human Genome Center at Beijing, Beijing, China.
85
National Institue of Cardiovascular Diseases, Karachi, Pakistan.
86
Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
87
Associazione per lo Studio della Trombosi in Cardiologia, Pavia, Italy.
88
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
89
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
90
Imperial College Healthcare NHS Trust, London, UK.
91
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
92
The Berlin Aging Study II; Research Group on Geriatrics; Charité - Universitätsmedizin Berlin, Berlin, Germany.
93
Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
94
Grupo de Epidemiología y Genética Cardiovascular, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
95
MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC, USA.
96
Division of Endocrinology and Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA.
97
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
98
Department of Cardiovascular Research, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
99
Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.
100
Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
101
Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
102
Cleveland Clinic, Cleveland, Ohio, USA.
103
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
104
Kaiser Permanente Division of Research, Oakland, California, USA.
105
Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands.
106
Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
107
Department of Forensic Medicine, University of Tampere School of Medicine, Tampere, Finland.
108
Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK.
109
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
110
The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, USA.
111
Department of Clinical Sciences, Hypertension and Cardiovascular Disease, Lund University, University Hospital Malmö, Malmö, Sweden.
112
Synlab Academy, Synlab Services GmbH, Mannheim, Germany.
113
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
114
Stanford Cardiovascular Institute, Stanford University, Stanford, California, USA.
115
Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
116
Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
117
University of Ottawa Heart Institute, Ottawa, Canada.
118
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
119
Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
120
Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
121
Oklahoma Center for Neuroscience, Oklahoma City, Oklahoma, USA.
122
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
123
Department of Epidemiology, University of Washington, Seattle, Washington, USA.
124
Department of Prosthetic Dentistry, Center for Dental and Oral Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
125
Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK.
126
Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Medical Faculty, Leipzig, Germany.
127
Harvard School of Public Health, Boston, Massachusetts, USA.
128
National Heart, Lung and Blood Institute Division of Intramural Research, Bethesda, Maryland, USA.
129
Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
130
Department of Health Sciences, University of Leicester, Leicester, UK.
131
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
#
Contributed equally

Abstract

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

PMID:
26343387
PMCID:
PMC4589895
DOI:
10.1038/ng.3396
[Indexed for MEDLINE]
Free PMC Article
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