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

doi:10.1038/ng.3843

Meta-Analysis

. 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

Ingrid E Christophersen^{1

2

3}, Michiel Rienstra⁴, Carolina Roselli^{1

5

6}, Xiaoyan Yin^{7

8}, Bastiaan Geelhoed⁴, John Barnard⁹, Honghuang Lin^{7

8}, Dan E Arking¹⁰, Albert V Smith^{11

12}, Christine M Albert^{13

14}, Mark Chaffin¹, Nathan R Tucker^{1

2}, Molong Li², Derek Klarin¹, Nathan A Bihlmeyer¹⁵, Siew-Kee Low¹⁶, Peter E Weeke^{17

18}, Martina Müller-Nurasyid^{5

19

20}, J Gustav Smith^{1

21}, Jennifer A Brody²², Maartje N Niemeijer²³, Marcus Dörr^{24

25}, Stella Trompet²⁶, Jennifer Huffman²⁷, Stefan Gustafsson²⁸, Claudia Schurmann^{29

30}, Marcus E Kleber³¹, Leo-Pekka Lyytikäinen³², Ilkka Seppälä³², Rainer Malik³³, Andrea R V R Horimoto³⁴, Marco Perez³⁵, Juha Sinisalo³⁶, Stefanie Aeschbacher^{37

38}, Sébastien Thériault^{39

40}, Jie Yao⁴¹, Farid Radmanesh^{1

42}, Stefan Weiss^{25

43}, Alexander Teumer^{25

44}, Seung Hoan Choi¹, Lu-Chen Weng^{1

2}, Sebastian Clauss^{2

19

20}, Rajat Deo⁴⁵, Daniel J Rader⁴⁵, Svati H Shah⁴⁶, Albert Sun⁴⁶, Jemma C Hopewell⁴⁷, Stephanie Debette^{48

49

50

51}, Ganesh Chauhan^{48

49}, Qiong Yang⁸, Bradford B Worrall⁵², Guillaume Paré^{39

40}, Yoichiro Kamatani¹⁶, Yanick P Hagemeijer⁴, Niek Verweij⁴, Joylene E Siland⁴, Michiaki Kubo⁵³, Jonathan D Smith⁹, David R Van Wagoner⁹, Joshua C Bis²², Siegfried Perz⁵⁴, Bruce M Psaty^{22

55

56

57

58}, Paul M Ridker^{13

14}, Jared W Magnani^{7

59}, Tamara B Harris⁶⁰, Lenore J Launer⁶⁰, M Benjamin Shoemaker¹⁷, Sandosh Padmanabhan⁶¹, Jeffrey Haessler⁶², Traci M Bartz^{22

63}, Melanie Waldenberger^{20

54

64}, Peter Lichtner⁶⁵, Marina Arendt⁶⁶, Jose E Krieger³⁴, Mika Kähönen⁶⁷, Lorenz Risch^{68

69}, Alfredo J Mansur⁷⁰, Annette Peters^{20

54

71}, Blair H Smith⁷², Lars Lind⁷³, Stuart A Scott⁷⁴, Yingchang Lu^{29

30}, Erwin B Bottinger^{29

75}, Jussi Hernesniemi^{32

76}, Cecilia M Lindgren⁷⁷, Jorge A Wong⁷⁸, Jie Huang⁷⁹, Markku Eskola⁷⁶, Andrew P Morris^{77

80}, Ian Ford⁸¹, Alex P Reiner^{55

61}, Graciela Delgado³¹, Lin Y Chen⁸², Yii-Der Ida Chen⁴¹, Roopinder K Sandhu⁸³, Man Li^{84

85}, Eric Boerwinkle⁸⁶, Lewin Eisele⁶⁶, Lars Lannfelt⁸⁷, Natalia Rost^{1

88}, Christopher D Anderson^{1

42}, Kent D Taylor⁴¹, Archie Campbell⁸⁹, Patrik K Magnusson⁹⁰, David Porteous⁸⁹, Lynne J Hocking⁹¹, Efthymia Vlachopoulou⁹², Nancy L Pedersen⁹⁰, Kjell Nikus⁷⁶, Marju Orho-Melander⁹³, Anders Hamsten⁹⁴, Jan Heeringa²³, Joshua C Denny¹⁷, Jennifer Kriebel^{54

64

71}, Dawood Darbar⁹⁵, Christopher Newton-Cheh^{1

2}, Christian Shaffer¹⁷, Peter W Macfarlane⁹⁶, Stefanie Heilmann-Heimbach^{97

98}, Peter Almgren⁹³, Paul L Huang², Nona Sotoodehnia⁵⁶, Elsayed Z Soliman⁹⁹, Andre G Uitterlinden¹⁰⁰, Albert Hofman²³, Oscar H Franco²³, Uwe Völker^{25

43}, Karl-Heinz Jöckel⁶⁶, Moritz F Sinner^{19

20}, Henry J Lin⁴¹, Xiuqing Guo⁴¹; METASTROKE Consortium of the ISGC; Neurology Working Group of the CHARGE Consortium; Martin Dichgans^{33

101

102}, Erik Ingelsson^{28

103}, Charles Kooperberg⁶², Olle Melander¹⁰⁴, Ruth J F Loos^{29

30

105}, Jari Laurikka¹⁰⁶, David Conen^{37

38

39}, Jonathan Rosand^{1

42}, Pim van der Harst⁴, Marja-Liisa Lokki⁹², Sekar Kathiresan¹, Alexandre Pereira^{107

108}, J Wouter Jukema^{26

109

110}, Caroline Hayward²⁷, Jerome I Rotter^{41

111}, Winfried März^{112

113}, Terho Lehtimäki³², Bruno H Stricker^{100

114}, Mina K Chung⁹, Stephan B Felix^{24

25}, Vilmundur Gudnason^{11

12}, Alvaro Alonso¹¹⁵, Dan M Roden¹⁷, Stefan Kääb^{19

20}, Daniel I Chasman^{1

13

116}, Susan R Heckbert^{55

56

57}, Emelia J Benjamin^{7

59

117}, Toshihiro Tanaka^{118

119}, Kathryn L Lunetta^{7

8}, Steven A Lubitz^{1

2

120}, Patrick T Ellinor^{1

2

120}; AFGen Consortium

Affiliations

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.

PMID: 28416818
PMCID: PMC5585859
DOI: 10.1038/ng.3843

Meta-Analysis

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

Ingrid E Christophersen et al. Nat Genet. 2017 Jun.

. 2017 Jun;49(6):946-952.

doi: 10.1038/ng.3843. Epub 2017 Apr 17.

Authors

Affiliations

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.

PMID: 28416818
PMCID: PMC5585859
DOI: 10.1038/ng.3843

Erratum in

Erratum: Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.
Christophersen IE, Rienstra M, Roselli C, Yin X, Geelhoed B, Barnard J, Lin H, Arking DE, Smith AV, Albert CM, Chaffin M, Tucker NR, Li M, Klarin D, Bihlmeyer NA, Low SK, Weeke PE, Müller-Nurasyid M, Smith JG, Brody JA, Niemeijer MN, Dörr M, Trompet S, Huffman J, Gustafsson S, Schurmann C, Kleber ME, Lyytikäinen LP, Seppälä I, Malik R, R V R Horimoto A, Perez M, Sinisalo J, Aeschbacher S, Thériault S, Yao J, Radmanesh F, Weiss S, Teumer A, Choi SH, Weng LC, Clauss S, Deo R, Rader DJ, Shah SH, Sun A, Hopewell JC, Debette S, Chauhan G, Yang Q, Worrall BB, Paré G, Kamatani Y, Hagemeijer YP, Verweij N, Siland JE, Kubo M, Smith JD, Van Wagoner DR, Bis JC, Perz S, Psaty BM, Ridker PM, Magnani JW, Harris TB, Launer LJ, Shoemaker MB, Padmanabhan S, Haessler J, Bartz TM, Waldenberger M, Lichtner P, Arendt M, Krieger JE, Kähönen M, Risch L, Mansur AJ, Peters A, Smith BH, Lind L, Scott SA, Lu Y, Bottinger EB, Hernesniemi J, Lindgren CM, Wong JA, Huang J, Eskola M, Morris AP, Ford I, Reiner AP, Delgado G, Chen LY, Chen YI, Sandhu RK, Li M, Boerwinkle E, Eisele L, Lannfelt L, Rost N, Anderson CD, Taylor KD, Campbell A, Magnusson PK, Porteous D, Hocking LJ, Vlachopoulou E, Pedersen NL, Nikus K,… See abstract for full author list ➔ Christophersen IE, et al. Nat Genet. 2017 Jul 27;49(8):1286. doi: 10.1038/ng0817-1286c. Nat Genet. 2017. PMID: 28747752 No abstract available.

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.

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Conflict of interest statement

Competing Financial Interests Statement

Dr. Ellinor is the PI on a grant from Bayer HealthCare to the Broad Institute focused on the genetics and therapeutics of atrial fibrillation. The remaining authors have no disclosures.

Figures

**Figure 1. Study flow-chart**
Overview of the approach employed for genome-wide and exome-wide association analyses.

**Figure 2. Manhattan plot of the combined ancestry GWAS meta-analyses**
Manhattan plot showing novel (red) and replicated (blue) genetic loci associated with atrial fibrillation in the combined ancestry GWAS meta-analysis. The dotted line represents the threshold of statistical significance (5×10⁻⁸). The gene names represent the gene in closest proximity to the most significant variant at each locus. There is a break in the Y-axis to increase the resolution of the genetic loci near the genome-wide significance threshold.

**Figure 3. Regional plots from combined ancestry GWAS meta-analysis**
The most significant variant at each locus is plotted (purple, diamond-shaped) and identified with rsID. Each dot in the plots represent a single variant present in our results and the color of the dot indicates the degree of linkage disequilibrium with the most significant variant, as shown on the top left color chart on each panel. The lower part of each panel shows the locations of genes at the respective loci. r², degree of linkage disequilibrium; chr, chromosome; Mb, megabases; cM, centiMorgan. Regional plots were created using LocusZoom.

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References

1. Chugh SS, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129:837–47. - PMC - PubMed
1. January CT, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64:2246–2280. - PubMed
1. Gudbjartsson DF, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448:353–357. - PubMed
1. Benjamin EJ, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet. 2009;41:879–81. - PMC - PubMed
1. Ellinor PT, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet. 2010;42:240–4. - PMC - PubMed

Online methods references

1. Benjamin EJ, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet. 2009;41:879–81. - PMC - PubMed
1. Willer CJ, Li Y, Abecasis GR. METAL: Fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–2191. - PMC - PubMed
1. Pe’er I, Yelensky R, Altshuler D, Daly MJ. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol. 2008;32:381–385. - PubMed
1. Hoggart CJ, Clark TG, De Iorio M, Whittaker JC, Balding DJ. Genome-wide significance for dense SNP and resequencing data. Genet Epidemiol. 2008;32:179–185. - PubMed
1. Dudbridge F, Gusnanto A. Estimation of significance thresholds for genomewide association scans. Genet Epidemiol. 2008;32:227–234. - PMC - PubMed

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[1] Chugh SS, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129:837–47. - PMC - PubMed

[2] Chugh SS, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129:837–47. - PMC - PubMed

[3] January CT, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64:2246–2280. - PubMed

[4] January CT, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64:2246–2280. - PubMed

[5] Gudbjartsson DF, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448:353–357. - PubMed

[6] Gudbjartsson DF, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448:353–357. - PubMed

[7] Benjamin EJ, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet. 2009;41:879–81. - PMC - PubMed

[8] Benjamin EJ, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet. 2009;41:879–81. - PMC - PubMed

[9] Ellinor PT, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet. 2010;42:240–4. - PMC - PubMed

[10] Ellinor PT, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet. 2010;42:240–4. - PMC - PubMed

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

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

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