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Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.

Multi-ethnic genome-wide association study for atrial fibrillation.

Roselli C1, Chaffin MD1, Weng LC1,2, Aeschbacher S3,4, Ahlberg G5,6,7, Albert CM8, Almgren P9, Alonso A10, Anderson CD1,11, Aragam KG1,11, Arking DE12, Barnard J13, Bartz TM14, Benjamin EJ15,16,17, Bihlmeyer NA18, Bis JC19, Bloom HL20, Boerwinkle E21, Bottinger EB22,23, Brody JA19, Calkins H24, Campbell A25, Cappola TP26, Carlquist J27,28, Chasman DI1,29, Chen LY30, Chen YI31, Choi EK32, Choi SH1, Christophersen IE1,2,33, Chung MK13, Cole JW34,35, Conen D3,4,36, Cook J37, Crijns HJ38, Cutler MJ27, Damrauer SM39,40, Daniels BR1, Darbar D41, Delgado G42, Denny JC43, Dichgans M44,45,46, Dörr M47,48, Dudink EA38, Dudley SC49, Esa N50, Esko T1,51, Eskola M52, Fatkin D53,54,55, Felix SB47,48, Ford I56, Franco OH57, Geelhoed B58, Grewal RP59,60, Gudnason V61,62, Guo X31, Gupta N1, Gustafsson S63, Gutmann R64, Hamsten A65, Harris TB66, Hayward C67, Heckbert SR68,69, Hernesniemi J52,70, Hocking LJ71, Hofman A57, Horimoto ARVR72, Huang J73, Huang PL2, Huffman J67, Ingelsson E63,74, Ipek EG24, Ito K75, Jimenez-Conde J76,77, Johnson R53, Jukema JW78,79,80, Kääb S81,82, Kähönen M83, Kamatani Y84, Kane JP85, Kastrati A82,86, Kathiresan S1,11, Katschnig-Winter P87, Kavousi M57, Kessler T86, Kietselaer BL38, Kirchhof P88,89,90, Kleber ME42, Knight S27,91, Krieger JE72, Kubo M92, Launer LJ66, Laurikka J93, Lehtimäki T70, Leineweber K94, Lemaitre RN19, Li M95,96, Lim HE97, Lin HJ31, Lin H15,16, Lind L98, Lindgren CM99, Lokki ML100, London B64, Loos RJF22,101,102, Low SK84, Lu Y22,101, Lyytikäinen LP70, Macfarlane PW103, Magnusson PK104, Mahajan A99, Malik R44, Mansur AJ105, Marcus GM106, Margolin L1, Margulies KB26, März W107,108, McManus DD50, Melander O109, Mohanty S110,111, Montgomery JA43, Morley MP26, Morris AP37, Müller-Nurasyid M81,82,112, Natale A110,111, Nazarian S113, Neumann B81, Newton-Cheh C1,11, Niemeijer MN57, Nikus K52, Nilsson P114, Noordam R115, Oellers H116, Olesen MS5,6,7, Orho-Melander M9, Padmanabhan S117, Pak HN118, Paré G36,119, Pedersen NL104, Pera J120, Pereira A121,122, Porteous D25, Psaty BM69,123, Pulit SL1,124,125, Pullinger CR85, Rader DJ126, Refsgaard L5,6,7, Ribasés M127,128,129, Ridker PM8, Rienstra M58, Risch L130,131, Roden DM43, Rosand J1,11, Rosenberg MA11,132, Rost N1,133, Rotter JI134, Saba S135, Sandhu RK136, Schnabel RB137,138, Schramm K81,112, Schunkert H82,86, Schurman C22,101, Scott SA139, Seppälä I70, Shaffer C43, Shah S140, Shalaby AA135,141, Shim J142, Shoemaker MB43, Siland JE58, Sinisalo J143, Sinner MF81,82, Slowik A120, Smith AV61,62, Smith BH144, Smith JG1,145, Smith JD13, Smith NL68,69, Soliman EZ146, Sotoodehnia N147, Stricker BH148,149, Sun A140, Sun H13, Svendsen JH5,7, Tanaka T150, Tanriverdi K50, Taylor KD31, Teder-Laving M51, Teumer A48,151, Thériault S36,119, Trompet S78,115, Tucker NR1,2, Tveit A33,152, Uitterlinden AG148, Van Der Harst P58, Van Gelder IC58, Van Wagoner DR13, Verweij N58, Vlachopoulou E100, Völker U48,153, Wang B154, Weeke PE5,43, Weijs B38, Weiss R155, Weiss S48,153, Wells QS43, Wiggins KL19, Wong JA156, Woo D157, Worrall BB158, Yang PS118, Yao J31, Yoneda ZT43, Zeller T137,138, Zeng L86, Lubitz SA1,2,159, Lunetta KL15,154, Ellinor PT160,161,162.

Author information

1
Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
2
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
3
University Hospital Basel, Basel, Switzerland.
4
Cardiovascular Research Institute Basel, Basel, Switzerland.
5
Laboratory for Molecular Cardiology, The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
6
The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
7
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
8
Divisions of Preventive and Cardiovascular Medicine, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
9
Department of Clinical Sciences, Lund University, Malmo, Sweden.
10
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
11
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
12
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
13
Departments of Cardiovascular Medicine, Cellular and Molecular Medicine, Molecular Cardiology, and Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA.
14
Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA, USA.
15
NHLBI and Boston University's Framingham Heart Study, Framingham, MA, USA.
16
Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
17
Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
18
Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
19
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
20
Division of Cardiology, Emory University and Atlanta VA Medical Center, Atlanta, GA, USA.
21
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
22
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
23
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
24
Johns Hopkins University, Baltimore, MD, USA.
25
Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
26
Penn Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
27
Intermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA.
28
Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT, USA.
29
Divisions of Preventive Medicine and Genetics, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
30
Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
31
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
32
Seoul National University Hospital, Seoul, Korea.
33
Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Drammen, Norway.
34
Baltimore Veterans Affairs Medical Center, Department of Neurology, Baltimore, MD, USA.
35
University of Maryland School of Medicine, Department of Neurology, Baltimore, MD, USA.
36
Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
37
Department of Biostatistics, University of Liverpool, Liverpool, UK.
38
Maastricht University Medical Center+ and Cardiovascular Research Institute Maastricht, Department of Cardiology, Maastricht, The Netherlands.
39
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
40
Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
41
University of Illinois Chicago, Chicago, IL, USA.
42
Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
43
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
44
Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
45
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
46
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
47
Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
48
DZHK (German Centre for Cardiovascular Research), partner site: Greifswald, Greifswald, Germany.
49
Cardiovascular Division and Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA.
50
University of Massachusetts Medical School Worcester, Worcester, MA, USA.
51
Estonian Genome Center, University of Tartu, Tartu, Estonia.
52
Heart Center, Department of Cardiology, Tampere University Hospital, Finland and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
53
Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
54
St Vincent's Hospital, Darlinghurst, New South Wales, Australia.
55
Faculty of Medicine, University of New South Wales, Kensington, New South Wales, Australia.
56
Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
57
Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
58
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
59
Dept. of Neuroscience, Saint Francis Medical Center, Trenton, NJ, USA.
60
School of Health and Medical Sciences, Seton Hall University, South Orange, NJ, USA.
61
Icelandic Heart Association, Kopavogur, Iceland.
62
Faculty of Medicine, University of Iceland, Reykavik, Iceland.
63
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
64
Division of Cardiovascular Medicine and Abboud Cardiovascular Research Center, University of Iowa, Iowa City, IA, USA.
65
Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
66
Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, MD, USA.
67
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
68
Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.
69
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
70
Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
71
Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
72
Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo, São Paulo, Brazil.
73
Boston VA Research Institute, Inc., Boston, MA, USA.
74
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
75
Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
76
Department of Neurology, Neurovascular Research Group IMIM-Hospital del Mar (Institut Hospital del Mar d'Investigacions Médiques), Barcelona, Spain.
77
Universitat Autònoma de Barcelona, Medicine Department, Barcelona, Spain.
78
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
79
Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands.
80
Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
81
Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University, Munich, Germany.
82
DZHK (German Centre for Cardiovascular Research), partner site: Munich Heart Alliance, Munich, Germany.
83
Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
84
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
85
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
86
Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, Munich, Germany.
87
Department of Neurology, Medical University of Graz, Graz, Austria.
88
Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK.
89
Sandwell and West Birmingham Hospitals NHS Trust and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
90
AFNET, Muenster, Germany.
91
Department of Medicine, University of Utah, Salt Lake City, UT, USA.
92
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
93
Department of Cardio-Thoracic Surgery, Heart Center, Tampere University Hospital, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
94
Dept. Disease Genomics, Bayer, Wuppertal, Germany.
95
Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
96
Division of Nephrology & Hypertension, Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT, USA.
97
Korea University Guro Hospital, Seoul, Korea.
98
Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
99
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
100
Transplantation Laboratory, Medicum, University of Helsinki, Helsinki, Finland.
101
The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
102
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
103
Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
104
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
105
Heart Institute, University of São Paulo, São Paulo, Brazil.
106
Division of Cardiology, University of California, San Francisco, San Francisco, California, USA.
107
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
108
Synlab Academy, Synlab Services GmbH, Mannheim, Germany.
109
Department of Internal Medicine, Clinical Sciences, Lund University, Malmo, Sweden.
110
Texas Cardiac Arrhythmia Institute, St David's Medical Center, Austin, TX, USA.
111
Dell Medical School, Austin, TX, USA.
112
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
113
University of Pennsylvania, Philadelphia, PA, USA.
114
Department of Clinical Sciences, Lund University and Skåne University Hospital, Malmo, Sweden.
115
Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
116
Atrial Fibrillation NETwork, Muenster, Germany.
117
Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
118
Yonsei University Health System, Seoul, Korea.
119
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
120
Department of Neurology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.
121
Laboratory of Genetics and Molecular Biology, Heart Institute, University of São Paulo, São Paulo, Brazil.
122
Department of Genetics, Harvard Medical School, Boston, MA, USA.
123
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.
124
Department of Genetics, Center for Molecular Medicine, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
125
Li Ka Shing Center for Health Information and Discovery, Big Data Institute, Oxford University, Oxford, UK.
126
Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
127
Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
128
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
129
Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
130
University Institute of Clinical Chemistry, University of Bern, Bern, Switzerland.
131
Labormedizinisches Zentrum Dr. Risch, Schaan, Liechtenstein.
132
University of Colorado School of Medicine, Aurora, CO, USA.
133
J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA, USA.
134
Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
135
Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA.
136
Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada.
137
Department of General and Interventional Cardiology, University Heart Centre Hamburg, Hamburg, Germany.
138
DZHK (German Centre for Cardiovascular Research), partner site: Hamburg/Kiel/Lübeck, Hamburg, Germany.
139
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
140
Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
141
Cardiology Division, Pittsburgh VA Healthcare System, Pittsburgh, Pennsylvania, USA.
142
Korea University Anam Hospital, Seoul, Korea.
143
Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.
144
Division of Population Health Sciences, University of Dundee, Dundee, UK.
145
Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
146
Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston Salem, NC, USA.
147
Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
148
Department of Epidemiology and Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
149
Inspectorate of Health Care, Utrecht, The Netherlands.
150
Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan.
151
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
152
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
153
Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
154
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
155
Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH, USA.
156
Division of Cardiology, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada.
157
University of Cincinnati College of Medicine, Cincinnati, OH, USA.
158
Departments of Neurology and Public Health Science, University of Virginia Health System, Charlottesville, VA, USA.
159
Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA.
160
Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. ellinor@mgh.harvard.edu.
161
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. ellinor@mgh.harvard.edu.
162
Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA. ellinor@mgh.harvard.edu.

Abstract

Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

PMID:
29892015
PMCID:
PMC6136836
DOI:
10.1038/s41588-018-0133-9
[Indexed for MEDLINE]
Free PMC Article

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