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Nat Genet. 2017 Jun;49(6):946-952. doi: 10.1038/ng.3843. Epub 2017 Apr 17.

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.

Christophersen IE1,2,3, Rienstra M4, Roselli C1,5,6, Yin X7,8, Geelhoed B4, Barnard J9, Lin H7,8, Arking DE10, Smith AV11,12, Albert CM13,14, Chaffin M1, Tucker NR1,2, Li M2, Klarin D1, Bihlmeyer NA15, Low SK16, Weeke PE17,18, Müller-Nurasyid M5,19,20, Smith JG1,21, Brody JA22, Niemeijer MN23, Dörr M24,25, Trompet S26, Huffman J27, Gustafsson S28, Schurmann C29,30, Kleber ME31, Lyytikäinen LP32, Seppälä I32, Malik R33, Horimoto ARVR34, Perez M35, Sinisalo J36, Aeschbacher S37,38, Thériault S39,40, Yao J41, Radmanesh F1,42, Weiss S25,43, Teumer A25,44, Choi SH1, Weng LC1,2, Clauss S2,19,20, Deo R45, Rader DJ45, Shah SH46, Sun A46, Hopewell JC47, Debette S48,49,50,51, Chauhan G48,49, Yang Q8, Worrall BB52, Paré G39,40, Kamatani Y16, Hagemeijer YP4, Verweij N4, Siland JE4, Kubo M53, Smith JD9, Van Wagoner DR9, Bis JC22, Perz S54, Psaty BM22,55,56,57,58, Ridker PM13,14, Magnani JW7,59, Harris TB60, Launer LJ60, Shoemaker MB17, Padmanabhan S61, Haessler J62, Bartz TM22,63, Waldenberger M20,54,64, Lichtner P65, Arendt M66, Krieger JE34, Kähönen M67, Risch L68,69, Mansur AJ70, Peters A20,54,71, Smith BH72, Lind L73, Scott SA74, Lu Y29,30, Bottinger EB29,75, Hernesniemi J32,76, Lindgren CM77, Wong JA78, Huang J79, Eskola M76, Morris AP77,80, Ford I81, Reiner AP55,61, Delgado G31, Chen LY82, Chen YI41, Sandhu RK83, Li M84,85, Boerwinkle E86, Eisele L66, Lannfelt L87, Rost N1,88, Anderson CD1,42, Taylor KD41, Campbell A89, Magnusson PK90, Porteous D89, Hocking LJ91, Vlachopoulou E92, Pedersen NL90, Nikus K76, Orho-Melander M93, Hamsten A94, Heeringa J23, Denny JC17, Kriebel J54,64,71, Darbar D95, Newton-Cheh C1,2, Shaffer C17, Macfarlane PW96, Heilmann-Heimbach S97,98, Almgren P93, Huang PL2, Sotoodehnia N56, Soliman EZ99, Uitterlinden AG100, Hofman A23, Franco OH23, Völker U25,43, Jöckel KH66, Sinner MF19,20, Lin HJ41, Guo X41; METASTROKE Consortium of the ISGC; Neurology Working Group of the CHARGE Consortium, Dichgans M33,101,102, Ingelsson E28,103, Kooperberg C62, Melander O104, Loos RJF29,30,105, Laurikka J106, Conen D37,38,39, Rosand J1,42, van der Harst P4, Lokki ML92, Kathiresan S1, Pereira A107,108, Jukema JW26,109,110, Hayward C27, Rotter JI41,111, März W112,113, Lehtimäki T32, Stricker BH100,114, Chung MK9, Felix SB24,25, Gudnason V11,12, Alonso A115, Roden DM17, Kääb S19,20, Chasman DI1,13,116, Heckbert SR55,56,57, Benjamin EJ7,59,117, Tanaka T118,119, Lunetta KL7,8, Lubitz SA1,2,120, Ellinor PT1,2,120; AFGen Consortium.

Author information

1
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2
Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
3
Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Rud, Norway.
4
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
5
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
6
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
7
NHLBI and Boston University's Framingham Heart Study, Framingham, Massachusetts, USA.
8
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
9
Departments of Cardiovascular Medicine, Cellular and Molecular Medicine, Molecular Cardiology, and Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA.
10
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
11
Icelandic Heart Association, Kopavogur, Iceland.
12
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
13
Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
14
Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
15
Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
16
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
17
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
18
Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
19
Department of Medicine I, University Hospital Munich, Ludwig Maximilians University, Munich, Germany.
20
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
21
Molecular Epidemiology and Cardiology, Clinical Sciences, Lund University, Lund, Sweden.
22
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
23
Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
24
Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
25
DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
26
Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
27
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
28
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
29
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
30
Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
31
Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
32
Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere, Finland.
33
Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany.
34
Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo, São Paulo, Brazil.
35
Department of Cardiovascular Medicine, Stanford University, Stanford, California, USA.
36
Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.
37
Department of Medicine, University Hospital Basel, Basel, Switzerland.
38
Cardiovascular Research Institute Basel, Basel, Switzerland.
39
Population Health Research Institute, Hamilton, Ontario, Canada.
40
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
41
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA.
42
Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
43
Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
44
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
45
Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
46
Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
47
CTSU-Nuffield Department of Population Health, University of Oxford, Oxford, UK.
48
INSERM U1219 (Bordeaux Population Health Centre), Bordeaux, France.
49
University of Bordeaux, Bordeaux, France.
50
Department of Neurology, Bordeaux University Hospital, Bordeaux, France.
51
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.
52
Departments of Neurology and Public Health Science, University of Virginia Health System, Charlottesville, Virginia, USA.
53
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
54
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
55
Department of Epidemiology, University of Washington, Seattle, Washington, USA.
56
Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.
57
Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.
58
Department of Health Services, University of Washington, Seattle, Washington, USA.
59
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
60
Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, Maryland, USA.
61
Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
62
Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA.
63
Cardiovascular Health Research Unit, Department of Biostatistics, University of Washington, Seattle, Washington, USA.
64
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
65
Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
66
Institute of Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany.
67
Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland.
68
University Institute of Clinical Chemistry, University of Bern, Bern, Switzerland.
69
Labormedizinisches Zentrum Dr. Risch, Schaan, Liechtenstein.
70
Heart Institute, University of São Paulo, São Paulo, Brazil.
71
German Center for Diabetes Research, Neuherberg, Germany.
72
Division of Population Health Sciences, University of Dundee, Dundee, UK.
73
Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
74
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
75
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
76
Department of Cardiology, Heart Hospital, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland.
77
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
78
Division of Cardiology, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada.
79
Boston VA Research Institute, Inc., Boston, Massachusetts, USA.
80
Department of Biostatistics, University of Liverpool, Liverpool, UK.
81
Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
82
Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
83
Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada.
84
Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA.
85
Division of Nephrology and Hypertension, Internal Medicine, School of Medicine, University of Utah, Salt Lake City, Utah, USA.
86
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
87
Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
88
Acute Stroke Services, Massachusetts General Hospital, Boston, Massachusetts, USA.
89
Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
90
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
91
Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen, Aberdeen, UK.
92
Transplantation Laboratory, Medicum, University of Helsinki, Helsinki, Finland.
93
Department of Clinical Sciences, Lund University, Malmö, Sweden.
94
Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
95
Department of Medicine and Pharmacology, University of Illinois, Chicago, Illinois, USA.
96
Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
97
Institute of Human Genetics, University of Bonn, Bonn, Germany.
98
Department of Genomics, Life and Brain Research Center, University of Bonn, Bonn, Germany.
99
Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
100
Department of Epidemiology and Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
101
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
102
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
103
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
104
Department of Internal Medicine, Clinical Sciences, Lund University, Malmö, Sweden.
105
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
106
Department of Cardio-Thoracic Surgery, Heart Hospital, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland.
107
Laboratory of Genetics and Molecular Biology, Heart Institute, University of São Paulo, São Paulo, Brazil.
108
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
109
Durrer Center for Cardiogenetic Research, Amsterdam, the Netherlands.
110
Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.
111
Institute for Translational Genomics and Population Sciences, Department of Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA.
112
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
113
Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim and Augsburg, Germany.
114
Inspectorate of Health Care, Utrecht, the Netherlands.
115
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
116
Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
117
Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA.
118
Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
119
Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan.
120
Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, USA.

Abstract

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

PMID:
28416818
PMCID:
PMC5585859
DOI:
10.1038/ng.3843
[Indexed for MEDLINE]
Free PMC Article

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