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J Am Coll Cardiol. 2017 Feb 21;69(7):823-836. doi: 10.1016/j.jacc.2016.11.056.

Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease.

Webb TR1, Erdmann J2, Stirrups KE3, Stitziel NO4, Masca NG1, Jansen H5, Kanoni S6, Nelson CP1, Ferrario PG7, König IR7, Eicher JD8, Johnson AD8, Hamby SE1, Betsholtz C9, Ruusalepp A10, Franzén O11, Schadt EE12, Björkegren JL13, Weeke PE14, Auer PL15, Schick UM16, Lu Y17, Zhang H18, Dube MP19, Goel A20, Farrall M20, Peloso GM21, Won HH22, Do R23, van Iperen E24, Kruppa J25, Mahajan A26, Scott RA27, Willenborg C28, Braund PS1, van Capelleveen JC29, Doney AS30, Donnelly LA30, Asselta R31, Merlini PA32, Duga S31, Marziliano N33, Denny JC34, Shaffer C35, El-Mokhtari NE36, Franke A37, Heilmann S38, Hengstenberg C39, Hoffmann P40, Holmen OL41, Hveem K42, Jansson JH43, Jöckel KH44, Kessler T5, Kriebel J45, Laugwitz KL46, Marouli E6, Martinelli N47, McCarthy MI48, Van Zuydam NR49, Meisinger C50, Esko T51, Mihailov E52, Escher SA53, Alver M54, Moebus S44, Morris AD55, Virtamo J56, Nikpay M57, Olivieri O47, Provost S58, AlQarawi A59, Robertson NR60, Akinsansya KO61, Reilly DF61, Vogt TF61, Yin W61, Asselbergs FW62, Kooperberg C63, Jackson RD64, Stahl E65, Müller-Nurasyid M66, Strauch K67, Varga TV53, Waldenberger M68; Wellcome Trust Case Control Consortium, Zeng L5, Chowdhury R69, Salomaa V56, Ford I70, Jukema JW71, Amouyel P72, Kontto J56; MORGAM Investigators, Nordestgaard BG73, Ferrières J74, Saleheen D75, Sattar N76, Surendran P77, Wagner A78, Young R69, Howson JM69, Butterworth AS79, Danesh J80, Ardissino D81, Bottinger EP82, Erbel R44, Franks PW83, Girelli D47, Hall AS84, Hovingh GK29, Kastrati A85, Lieb W86, Meitinger T87, Kraus WE88, Shah SH88, McPherson R57, Orho-Melander M89, Melander O90, Metspalu A54, Palmer CN30, Peters A91, Rader DJ92, Reilly MP93, Loos RJ94, Reiner AP95, Roden DM96, Tardif JC19, Thompson JR97, Wareham NJ27, Watkins H20, Willer CJ98, Samani NJ99, Schunkert H5, Deloukas P100, Kathiresan S101; Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators.

Author information

1
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
2
Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany; DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany; University Heart Center Luebeck, Lübeck, Germany.
3
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
4
Cardiovascular Division, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri; Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri; McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, Missouri.
5
Deutsches Herzzentrum München, Technische Universität München, München, Germany; DZHK, Partner Site Munich Heart Alliance, Munich, Germany.
6
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
7
DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany; Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany.
8
Center for Population Studies, National Heart, Lung, and Blood Institute, The Framingham Heart Study, Framingham, Massachusetts.
9
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden; Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm, Sweden.
10
Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu, Estonia; Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia; Clinical Gene Networks AB, Stockholm, Sweden.
11
Clinical Gene Networks AB, Stockholm, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
12
Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
13
Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm, Sweden; Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu, Estonia; Clinical Gene Networks AB, Stockholm, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
14
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
15
School of Public Heath, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin.
16
Fred Hutchinson Cancer Research Center, Seattle, Washington; The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York.
17
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York.
18
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan.
19
Université de Montréal, Faculté de médecine, Département de médecine, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada.
20
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
21
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
22
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea.
23
The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York; The Center for Statistical Genetics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; The Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; The Zena and Michael A. Weiner Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
24
Department of Biostatistics, Academic Medical Center, Amsterdam, the Netherlands.
25
Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany.
26
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
27
MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.
28
Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.
29
Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
30
Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Scotland, United Kingdom.
31
Department of Biomedical Sciences, Humanitas University, Milan, Italy; Humanitas Clinical and Research Center, Milan, Italy.
32
Niguarda Hospital, Milan, Italy.
33
Azienda Sanitaria Locale 3 San Francesco, Nuoro, Italy 3, Nuoro, Italy.
34
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Biomedical informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
35
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
36
Klinik für Kardiologie, Pneumologie und Innere Medizin, Imland Klinik Rendsburg, Rendsburg, Germany.
37
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
38
Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
39
McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, Missouri; Deutsches Herzzentrum München, Technische Universität München, München, Germany.
40
Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany; Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
41
HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway; St. Olav Hospital, Trondheim University Hospital, Trondheim, Norway.
42
HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway; Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway.
43
Department of Public Health and Clinical Medicine, Research Unit Skellefteå, Umeå University, Sweden.
44
Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany.
45
Research unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany.
46
DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute Medizinische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
47
Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy.
48
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Old Road Headington, Oxford, Oxford, United Kingdom.
49
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
50
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
51
Estonian Genome Center, University of Tartu, Tartu, Estonia; Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts; Department of Genetics, Harvard Medical School, Boston, Massachusetts; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.
52
Estonian Genome Center, University of Tartu, Tartu, Estonia.
53
Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden.
54
Estonian Genome Center, University of Tartu, Tartu, Estonia; Institute of Molecular and Cell Biology, Tartu, Estonia.
55
School of Molecular, Genetic and Population Health Sciences, University of Edinburgh, Medical School, Teviot Place, Edinburgh, Scotland, United Kingdom.
56
National Institute for Health and Welfare (THL), Helsinki, Finland.
57
Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
58
Montreal Heart Institute, Montreal, Quebec, Canada.
59
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
60
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
61
Merck Sharp & Dohme, Rahway, New Jersey.
62
Department of Cardiology, Division Heart & Lungs, UMC Utrecht, the Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom.
63
Fred Hutchinson Cancer Research Center, Seattle, Washington.
64
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Ohio State University, Columbus, Ohio.
65
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
66
DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
67
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
68
Research unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
69
MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
70
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom.
71
Department of Cardiology, Leiden University Medical Center, Leiden and Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.
72
Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE, Lille, France.
73
Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
74
Toulouse University School of Medicine, Toulouse, France.
75
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Noncommunicable Diseases, Karachi, Pakistan.
76
British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
77
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
78
Department of Epîdemiology and Public Health, University of Strasbourg, Strasbourg, France.
79
MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; National Institute of Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom.
80
MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; National Institute of Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
81
Parma University Hospital, Parma, Italy.
82
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York.
83
Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts; Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden.
84
Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom.
85
Deutsches Herzzentrum München, Technische Universität München, München, Germany.
86
Institute of Epidemiology and Biobank popgen, Christian-Albrechts-University Kiel, Kiel, Germany.
87
DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany.
88
Duke Molecular Physiology Institute, Duke University, Durham, North Carolina; Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina.
89
Department of Clinical Sciences in Malmo, Lund University, Clinical Research Center, Malmo, Sweden.
90
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmo, Malmo, Sweden.
91
DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
92
Department of Genetics, Cardiovascular Institute and Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
93
Division of Cardiology, Department of Medicine and the Irving Institute for Clinical and Translational Research, Columbia University, New York, New York.
94
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York; The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York.
95
Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington.
96
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
97
NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom; Department of Health Sciences, University of Leicester, Leicester, United Kingdom.
98
Université de Montréal, Faculté de médecine, Département de médecine, Montreal, Quebec, Canada; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan.
99
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. Electronic address: njs@le.ac.uk.
100
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address: p.deloukas@qmul.ac.uk.
101
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts.

Abstract

BACKGROUND:

Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.

OBJECTIVES:

This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci.

METHODS:

In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs.

RESULTS:

We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10-4 with a range of other diseases/traits.

CONCLUSIONS:

We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

KEYWORDS:

cholesteryl ester transfer protein; expression quantitative trait loci; genetics; genome-wide association; single nucleotide polymorphism

PMID:
28209224
PMCID:
PMC5314135
DOI:
10.1016/j.jacc.2016.11.056
[Indexed for MEDLINE]
Free PMC Article

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