Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases

Carolina Roselli^#^{1

2}, Ida Surakka^#³, Morten S Olesen^#⁴, Gardar Sveinbjornsson^#⁵, Nicholas A Marston^#^{6

7}, Seung Hoan Choi¹, Hilma Holm⁵, Mark Chaffin¹, Daniel Gudbjartsson^{5

8}, Matthew C Hill^{1

9}, Hildur Aegisdottir⁵, Christine M Albert^{10

11}, Alvaro Alonso¹², Christopher D Anderson^{13

14}, Dan E Arking¹⁵, David O Arnar^{5

16

17}, John Barnard¹⁸, Emelia J Benjamin^{19

20

21}, Eugene Braunwald^{6

7}, Ben Brumpton^{22

23}, Archie Campbell²⁴, Nathalie Chami^{25

26}, Daniel I Chasman^{11

27}, Kelly Cho^{28

29}, Eue-Keun Choi³⁰, Ingrid E Christophersen^{31

32}, Mina K Chung³³, David Conen³⁴, Harry J Crijns³⁵, Michael J Cutler³⁶, Tomasz Czuba^{37

38}, Scott M Damrauer^{39

40

41}, Martin Dichgans^{42

43}, Marcus Dörr^{44

45}, Elton Dudink³⁵, ThuyVy Duong¹⁵, Christian Erikstrup^{46

47}, Tõnu Esko⁴⁸, Diane Fatkin^{49

50

51}, Jessica D Faul⁵², Manuel Ferreira⁵³, Daniel F Freitag⁵⁴, Santhi K Ganesh^{55

56}, J Michael Gaziano^{57

58}, Bastiaan Geelhoed², Jonas Ghouse^{4

59}, Christian Gieger⁶⁰, Franco Giulianini¹¹, Sarah E Graham³, Vilmundur Gudnason^{16

61}, Xiuqing Guo^{62

63}, Christopher Haggerty⁶⁴, Caroline Hayward⁶⁵, Susan R Heckbert^{66

67}, Kristian Hveem²², Kaoru Ito⁶⁸, Renee Johnson^{49

50}, J Wouter Jukema^{69

70}, Sean J Jurgens^{1

71}, Stefan Kääb^{72

73}, John P Kane⁷⁴, Shinwan Kany^{1

75

76}, Sharon L R Kardia⁷⁷, Maryam Kavousi⁷⁸, Shaan Khurshid^{1

79}, Frederick K Kamanu^{6

7}, Paulus Kirchhof^{75

76

80

81}, Marcus E Kleber^{82

83}, Stacey Knight^{36

84}, Issei Komuro^{85

86}, Jose E Krieger⁸⁷, Lenore J Launer⁸⁸, Dadong Li⁵³, Honghuang Lin⁸⁹, Henry J Lin^{62

63}, Ruth J F Loos^{25

90}, Luca Lotta⁵³, Steven A Lubitz^{1

79}, Kathryn L Lunetta⁹¹, Peter W Macfarlane^{92

93}, Patrik K E Magnusson⁹⁴, Rainer Malik^{42

43}, Helene Mantineo⁹⁵, Gregory M Marcus⁹⁶, Winfried März^{83

97}, David D McManus⁹⁸, Olle Melander⁹⁹, Giorgio E M Melloni⁶, Pascal B Meyre¹⁰⁰, Kazuo Miyazawa⁶⁸, Sanghamitra Mohanty¹⁰¹, Laia M Monfort^{4

59}, Martina Müller-Nurasyid^{102

103}, Navid A Nafissi¹⁰⁴, Andrea Natale^{101

105}, Saman Nazarian¹⁰⁶, Sisse R Ostrowski^{107

108}, Hui-Nam Pak¹⁰⁹, Shichao Pang¹¹⁰, Ole B Pedersen¹¹¹, Nancy L Pedersen⁹⁴, Alexandre C Pereira⁸⁷, James P Pirruccello¹, Michael Preuss²⁵, Bruce M Psaty¹¹², Clive R Pullinger¹¹³, Daniel J Rader¹¹⁴, Joel T Rämö^{1

9

115}, Paul M Ridker^{11

27}, Michiel Rienstra², Lorenz Risch^{116

117}, Dan M Roden¹¹⁸, Jerome I Rotter^{62

119}, Marc S Sabatine^{6

7}, Heribert Schunkert^{110

120}, Svati H Shah¹⁰⁴, Jaemin Shim¹²¹, M Benjamin Shoemaker¹²², Bridget Simonson¹, Moritz F Sinner^{72

73}, Roelof A J Smit²⁵, Jennifer A Smith^{52

77}, Nicholas L Smith^{66

67

123}, J Gustav Smith^{37

38}, Elsayed Z Soliman¹²⁴, Erik Sørensen¹⁰⁷, Nona Sotoodehnia¹²⁵, Daniel Strbian¹²⁶, Bruno H Stricker⁷⁸, Maris Teder-Laving⁴⁸, Yan V Sun^{12

127}, Sébastien Thériault^{34

128}, Rosa B Thorolfsdottir⁵, Unnur Thorsteinsdottir^{5

16}, Arnljot Tveit^{31

129}, Pim van der Harst¹³⁰, Joyce van Meurs^{78

131}, Biqi Wang⁹¹, Stefan Weiss^{45

132}, Quinn S Wells¹¹⁸, Lu-Chen Weng^{1

133

134}, Peter W Wilson^{12

135

136}, Ling Xiao^{1

9}, Pil-Sung Yang¹³⁷, Jie Yao⁶², Zachary T Yoneda¹²², Tanja Zeller^{76

138}, Lingyao Zeng⁵⁴, Wei Zhao^{52

77}, Xiang Zhou¹³⁹, Sebastian Zöllner¹⁴⁰; BioBank Japan Project; Regeneron Genetics Center; DBDS Genomic Consortium; Christian T Ruff^{6

7}, Henning Bundgaard^{59

108}, Cristen Willer^{3

141}, Kari Stefansson^{5

16}, Patrick T Ellinor^{142

143

144}

Affiliations

¹ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³ Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵ deCODE genetics/Amgen Inc., Reykjavik, Iceland.
⁶ TIMI Study Group, Boston, MA, USA.
⁷ Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
⁹ Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Cardiology, Cedars-Sinai, Los Angeles, CA, USA.
¹¹ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹² Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
¹³ Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
¹⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁵ McKusick Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁶ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁷ Cardiovascular Centre, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.
¹⁸ Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁹ Department of Medicine, Boston Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
²⁰ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
²¹ Framingham Heart Study, Framingham, MA, USA.
²² K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
²³ Clinic of Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
²⁴ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
²⁵ Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁶ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁷ Harvard Medical School, Boston, MA, USA.
²⁸ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
²⁹ Division of Aging, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³⁰ Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
³¹ Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Gjettum, Norway.
³² Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
³³ Cardiovascular Medicine, Heart Vascular and Thoracic Institute and Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA.
³⁴ Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
³⁵ Department of Cardiology and CARIM, Maastricht University Medical Centre, Maastricht, The Netherlands.
³⁶ Intermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA.
³⁷ The Wallenberg Laboratory/Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University and the Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
³⁸ Department of Cardiology, Lund University Diabetes Center, Wallenberg Center for Molecular Medicine, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
³⁹ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁰ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴¹ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
⁴² Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
⁴³ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴⁴ Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
⁴⁵ German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany.
⁴⁶ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
⁴⁷ Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
⁴⁸ Institute of Genomics, University of Tartu, Tartu, Estonia.
⁴⁹ Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
⁵⁰ UNSW Sydney, Sydney, New South Wales, Australia.
⁵¹ St Vincent's Hospital, Sydney, New South Wales, Australia.
⁵² Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁵³ Regeneron Genetics Center, Tarrytown, NY, USA.
⁵⁴ Bayer Pharmaceuticals, Wuppertal, Germany.
⁵⁵ Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
⁵⁶ Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
⁵⁷ Million Veteran Program, VA Boston Healthcare System, Boston, MA, USA.
⁵⁸ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵⁹ Department of Cardiology, Copenhagen University Hospital, Copenhagen, Denmark.
⁶⁰ Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁶¹ Icelandic Heart Association, Kópavogur, Iceland.
⁶² Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁶³ Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
⁶⁴ Department of Translational Data Science and Informatics, Geisinger, Danville, PA, USA.
⁶⁵ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
⁶⁶ Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁶⁷ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁶⁸ Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁶⁹ Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands.
⁷⁰ Netherlands Heart Institute, Utrecht, The Netherlands.
⁷¹ Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
⁷² Department of Cardiology, University Hospital, LMU Munich, Munich, Germany.
⁷³ German Centre for Cardiovascular Research (DZHK), Partner site: Munich Heart Alliance, Munich, Germany.
⁷⁴ Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
⁷⁵ Department of Cardiology, University Heart and Vascular Center UKE Hamburg, Hamburg, Germany.
⁷⁶ German Center for Cardiovascular Research (DZHK), Hamburg, Germany.
⁷⁷ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁷⁸ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁷⁹ Demoulas Center for Cardiac Arrhythmias and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
⁸⁰ Institute of Cardiovascular Sciences, Birmingham, UK.
⁸¹ AFNET, Münster, Germany.
⁸² SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany.
⁸³ Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
⁸⁴ Department of Medicine, School of Medicine, University of Utah, Salt Lake City, UT, USA.
⁸⁵ International University of Health and Welfare, Tokyo, Japan.
⁸⁶ Department of Frontier Cardiovascular Science, The University of Tokyo, Tokyo, Japan.
⁸⁷ Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of Sao Paulo, Sao Paulo, Brazil.
⁸⁸ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
⁸⁹ Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
⁹⁰ Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁹¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁹² School of Health and Wellbeing, University of Glasgow, Glasgow, Scotland, UK.
⁹³ Electrocardiology Group, New Lister Building, Royal Infirmary, Glasgow, Scotland, UK.
⁹⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁹⁵ Precision Cardiology Laboratory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹⁶ Division of Cardiology, University of California, San Francisco, CA, USA.
⁹⁷ Synlab Academy, SYNLAB Holding Deutschland GmbH, Mannheim, Germany.
⁹⁸ University of Massachusetts Medical School, Worcester, MA, USA.
⁹⁹ Department of Internal Medicine, Lund University and Skåne University Hospital, Malmö, Sweden.
¹⁰⁰ Cardiovascular Research Institute Basel (CRIB), University Hospital Basel, Basel, Switzerland.
¹⁰¹ Texas Cardiac Arrhythmia Institute, Austin, TX, USA.
¹⁰² IBE, Faculty of Medicine, LMU Munich, Munich, Germany.
¹⁰³ Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany.
¹⁰⁴ Division of Cardiology, Duke University School of Medicine, Durham, NC, USA.
¹⁰⁵ Department of Biomedicine and Prevention, Division of Cardiology, University of Tor Vergata, Rome, Italy.
¹⁰⁶ Section of Cardiac Electrophysiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁰⁷ Department of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁰⁸ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹⁰⁹ Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea.
¹¹⁰ Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
¹¹¹ Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.
¹¹² Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Systems and Population Health, University of Washington, Seattle, WA, USA.
¹¹³ Cardiovascular Research Institute and Department of Physiological Nursing, University of California, San Francisco, CA, USA.
¹¹⁴ Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹¹⁵ Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
¹¹⁶ Institute of Laboratory Medicine, Faculty of Medical Sciences, Private University of the Principality of Liechtenstein, Triesen, Liechtenstein.
¹¹⁷ Center of Laboratory Medicine, University Institute of Clinical Chemistry, University of Bern, Inselspital, Bern, Switzerland.
¹¹⁸ Departments of Medicine Pharmacology and Biomedical Informatics, Divisions of Cardiovascular Medicine and Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹¹⁹ Departments of Pediatrics and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
¹²⁰ Deutsches Zentrum für Herz- und Kreislauferkrankungen (DZHK), Partner site: Munich Heart Alliance, Munich, Germany.
¹²¹ Korea University Cardiovascular Center, Seoul, Republic of Korea.
¹²² Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹²³ Seattle Epidemiologic Research and Information Center, VA Puget Sound Health Care System, Seattle, WA, USA.
¹²⁴ Epidemiological Cardiology Research Center, Section on Cardiovascular Medicine, Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹²⁵ Division of Cardiology, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
¹²⁶ Department of Neurology and Neurosciences, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
¹²⁷ Atlanta VA Health Care System, Decatur, GA, USA.
¹²⁸ Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec City, Québec, Canada.
¹²⁹ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹³⁰ Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
¹³¹ Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹³² Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
¹³³ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
¹³⁴ VA Boston Healthcare System, Boston, MA, USA.
¹³⁵ Atlanta VA Medical Center, Atlanta, GA, USA.
¹³⁶ Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
¹³⁷ Cha University College of Medicine, Seoul, Republic of Korea.
¹³⁸ University Center of Cardiovascular Sciences, Department of Cardiology, University Heart & Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹³⁹ Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
¹⁴⁰ Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
¹⁴¹ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
¹⁴² Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ellinor@mgh.harvard.edu.
¹⁴³ Demoulas Center for Cardiac Arrhythmias and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. ellinor@mgh.harvard.edu.
¹⁴⁴ Heart and Vascular Institute, Mass General Brigham, Boston, MA, USA. ellinor@mgh.harvard.edu.

^# Contributed equally.

PMID: 40050429
PMCID: PMC12094172 (available on 2026-03-06)
DOI: 10.1038/s41588-024-02072-3

Meta-Analysis

Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases

Carolina Roselli et al. Nat Genet. 2025 Mar.

. 2025 Mar;57(3):539-547.

doi: 10.1038/s41588-024-02072-3. Epub 2025 Mar 6.

Authors

Affiliations

¹ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³ Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵ deCODE genetics/Amgen Inc., Reykjavik, Iceland.
⁶ TIMI Study Group, Boston, MA, USA.
⁷ Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
⁹ Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Cardiology, Cedars-Sinai, Los Angeles, CA, USA.
¹¹ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹² Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
¹³ Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
¹⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁵ McKusick Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁶ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁷ Cardiovascular Centre, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.
¹⁸ Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁹ Department of Medicine, Boston Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
²⁰ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
²¹ Framingham Heart Study, Framingham, MA, USA.
²² K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
²³ Clinic of Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
²⁴ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
²⁵ Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁶ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁷ Harvard Medical School, Boston, MA, USA.
²⁸ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
²⁹ Division of Aging, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³⁰ Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
³¹ Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Gjettum, Norway.
³² Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
³³ Cardiovascular Medicine, Heart Vascular and Thoracic Institute and Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA.
³⁴ Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
³⁵ Department of Cardiology and CARIM, Maastricht University Medical Centre, Maastricht, The Netherlands.
³⁶ Intermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA.
³⁷ The Wallenberg Laboratory/Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University and the Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
³⁸ Department of Cardiology, Lund University Diabetes Center, Wallenberg Center for Molecular Medicine, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
³⁹ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁰ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴¹ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
⁴² Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
⁴³ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴⁴ Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
⁴⁵ German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany.
⁴⁶ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
⁴⁷ Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
⁴⁸ Institute of Genomics, University of Tartu, Tartu, Estonia.
⁴⁹ Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
⁵⁰ UNSW Sydney, Sydney, New South Wales, Australia.
⁵¹ St Vincent's Hospital, Sydney, New South Wales, Australia.
⁵² Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁵³ Regeneron Genetics Center, Tarrytown, NY, USA.
⁵⁴ Bayer Pharmaceuticals, Wuppertal, Germany.
⁵⁵ Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
⁵⁶ Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
⁵⁷ Million Veteran Program, VA Boston Healthcare System, Boston, MA, USA.
⁵⁸ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵⁹ Department of Cardiology, Copenhagen University Hospital, Copenhagen, Denmark.
⁶⁰ Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁶¹ Icelandic Heart Association, Kópavogur, Iceland.
⁶² Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁶³ Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
⁶⁴ Department of Translational Data Science and Informatics, Geisinger, Danville, PA, USA.
⁶⁵ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
⁶⁶ Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁶⁷ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁶⁸ Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁶⁹ Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands.
⁷⁰ Netherlands Heart Institute, Utrecht, The Netherlands.
⁷¹ Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
⁷² Department of Cardiology, University Hospital, LMU Munich, Munich, Germany.
⁷³ German Centre for Cardiovascular Research (DZHK), Partner site: Munich Heart Alliance, Munich, Germany.
⁷⁴ Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
⁷⁵ Department of Cardiology, University Heart and Vascular Center UKE Hamburg, Hamburg, Germany.
⁷⁶ German Center for Cardiovascular Research (DZHK), Hamburg, Germany.
⁷⁷ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁷⁸ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁷⁹ Demoulas Center for Cardiac Arrhythmias and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
⁸⁰ Institute of Cardiovascular Sciences, Birmingham, UK.
⁸¹ AFNET, Münster, Germany.
⁸² SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany.
⁸³ Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
⁸⁴ Department of Medicine, School of Medicine, University of Utah, Salt Lake City, UT, USA.
⁸⁵ International University of Health and Welfare, Tokyo, Japan.
⁸⁶ Department of Frontier Cardiovascular Science, The University of Tokyo, Tokyo, Japan.
⁸⁷ Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of Sao Paulo, Sao Paulo, Brazil.
⁸⁸ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
⁸⁹ Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
⁹⁰ Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁹¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁹² School of Health and Wellbeing, University of Glasgow, Glasgow, Scotland, UK.
⁹³ Electrocardiology Group, New Lister Building, Royal Infirmary, Glasgow, Scotland, UK.
⁹⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁹⁵ Precision Cardiology Laboratory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹⁶ Division of Cardiology, University of California, San Francisco, CA, USA.
⁹⁷ Synlab Academy, SYNLAB Holding Deutschland GmbH, Mannheim, Germany.
⁹⁸ University of Massachusetts Medical School, Worcester, MA, USA.
⁹⁹ Department of Internal Medicine, Lund University and Skåne University Hospital, Malmö, Sweden.
¹⁰⁰ Cardiovascular Research Institute Basel (CRIB), University Hospital Basel, Basel, Switzerland.
¹⁰¹ Texas Cardiac Arrhythmia Institute, Austin, TX, USA.
¹⁰² IBE, Faculty of Medicine, LMU Munich, Munich, Germany.
¹⁰³ Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany.
¹⁰⁴ Division of Cardiology, Duke University School of Medicine, Durham, NC, USA.
¹⁰⁵ Department of Biomedicine and Prevention, Division of Cardiology, University of Tor Vergata, Rome, Italy.
¹⁰⁶ Section of Cardiac Electrophysiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁰⁷ Department of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁰⁸ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹⁰⁹ Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea.
¹¹⁰ Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
¹¹¹ Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.
¹¹² Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Systems and Population Health, University of Washington, Seattle, WA, USA.
¹¹³ Cardiovascular Research Institute and Department of Physiological Nursing, University of California, San Francisco, CA, USA.
¹¹⁴ Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹¹⁵ Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
¹¹⁶ Institute of Laboratory Medicine, Faculty of Medical Sciences, Private University of the Principality of Liechtenstein, Triesen, Liechtenstein.
¹¹⁷ Center of Laboratory Medicine, University Institute of Clinical Chemistry, University of Bern, Inselspital, Bern, Switzerland.
¹¹⁸ Departments of Medicine Pharmacology and Biomedical Informatics, Divisions of Cardiovascular Medicine and Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹¹⁹ Departments of Pediatrics and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
¹²⁰ Deutsches Zentrum für Herz- und Kreislauferkrankungen (DZHK), Partner site: Munich Heart Alliance, Munich, Germany.
¹²¹ Korea University Cardiovascular Center, Seoul, Republic of Korea.
¹²² Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹²³ Seattle Epidemiologic Research and Information Center, VA Puget Sound Health Care System, Seattle, WA, USA.
¹²⁴ Epidemiological Cardiology Research Center, Section on Cardiovascular Medicine, Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹²⁵ Division of Cardiology, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
¹²⁶ Department of Neurology and Neurosciences, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
¹²⁷ Atlanta VA Health Care System, Decatur, GA, USA.
¹²⁸ Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec City, Québec, Canada.
¹²⁹ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹³⁰ Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
¹³¹ Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹³² Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
¹³³ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
¹³⁴ VA Boston Healthcare System, Boston, MA, USA.
¹³⁵ Atlanta VA Medical Center, Atlanta, GA, USA.
¹³⁶ Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
¹³⁷ Cha University College of Medicine, Seoul, Republic of Korea.
¹³⁸ University Center of Cardiovascular Sciences, Department of Cardiology, University Heart & Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹³⁹ Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
¹⁴⁰ Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
¹⁴¹ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
¹⁴² Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ellinor@mgh.harvard.edu.
¹⁴³ Demoulas Center for Cardiac Arrhythmias and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. ellinor@mgh.harvard.edu.
¹⁴⁴ Heart and Vascular Institute, Mass General Brigham, Boston, MA, USA. ellinor@mgh.harvard.edu.

^# Contributed equally.

PMID: 40050429
PMCID: PMC12094172 (available on 2026-03-06)
DOI: 10.1038/s41588-024-02072-3

Abstract

Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.

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Conflict of interest statement

Competing interests: B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. C.D.A. receives sponsored research support from Bayer AG and has consulted for ApoPharma. C. Haggerty receives research support from Tempus Labs, outside the scope of the present work. C.M.A. receives sponsored research support from St. Jude, Abbott and Roche. C.R. is supported by a grant from Bayer AG to the Broad Institute focused on the development of therapeutics for cardiovascular disease. C.R. is a full-time employee of GSK as of 1 July 2024. C.T.R. reports research grants through Brigham and Women’s Hospital from Amgen, Anthos, AstraZeneca, Daiichi Sankyo, Janssen, Merck and Novartis and has received honoraria for scientific advisory boards and consulting from Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Pfizer, Regeneron and Sirius. The spouse of C.W. works at Regeneron Pharmaceuticals. D.O.A., D.G., G. Sveinbjornsson, H.A., H.H., K.S., R.B.T. and U.T. are employees of deCODE genetics/Amgen. D.C. has received consultancy fees from Roche Diagnostics and Trimedics, and speaker’s fees from BMS/Pfizer and Servier, all outside of the current work. D.F.F. is a full-time employee of Bayer. E.B. performs uncompensated consultancies and lectures with The Medicines Company. E.-K.C. reports research grants or speaking fees from Abbott, Bayer, BMS/Pfizer, Biosense Webster, Chong Kun Dang, Daewoong Pharmaceutical, Daiichi Sankyo, DeepQure, Dreamtech, Jeil Pharmaceutical, Medtronic, Samjinpharm, Seers Technology and Skylabs. L.-C.W. receives sponsored research support from IBM to the Broad Institute. L.Z. is a full-time employee of Bayer AG. M.E.K. is employed by SYNLAB Holding Deutschland. M.S.S. receives research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Intarcia, Ionis, Medicines Company, MedImmune, Merck, Novartis, Pfizer and Quark Pharmaceuticals and consults for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol Myers Squibb, DalCor, Dr. Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk and Silence Therapeutics; additionally, M.S.S. is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from ARCA Biopharma, Janssen Research and Development, Siemens Healthcare Diagnostics, Softcell Medical Limited, Regeneron, Roche and Zora Biosciences. N.A.M. reports involvement in clinical trials with Amgen, Pfizer, Ionis, Novartis and AstraZeneca without personal fees, payments or increase in salary. P.M.R. has received investigator-initiated research grant support for unrelated projects from NHLBI, Operation Warp Speed, Novartis, Kowa, Amarin and Pfizer and has served as a consultant on unrelated issues to Novo Nordisk, Flame, Agepha, Uppton, Novartis, Jansen, Health Outlook, Civi Biopharm, Alnylam and SOCAR. P.T.E. receives sponsored research support from Bayer AG, Bristol Myers Squibb, Pfizer and Novo Nordisk; he has also served on advisory boards or consulted for Bayer AG. S.A.L. is a full-time employee of Novartis Institutes for BioMedical Research as of 18 July 2022. Previously, S.A.L. received sponsored research support from Bristol Myers Squibb/Pfizer, Bayer, Boehringer Ingelheim, Fitbit, IBM, Medtronic and Premier, and consulted for Bristol Myers Squibb/Pfizer, Bayer, Blackstone Life Sciences and Invitae. S.M.D. receives research support from RenalytixAI and personal consulting fees from Calico Labs, outside the scope of the current research. W.M. reports grants and/or personal fees from Siemens Healthineers, Aegerion Pharmaceuticals, AMGEN, AstraZeneca, Sanofi, Alexion Pharmaceuticals, BASF, Abbott Diagnostics, Numares, Berlin-Chemie, Akzea Therapeutics, Bayer Vital, bestbion dx, Boehringer Ingelheim Pharma, Immundiagnostik, Merck Chemicals, MSD Sharp and Dohme, Novartis Pharma and Olink Proteomics, and other from Synlab Holding Deutschland, all outside the submitted work. A.N. is a consultant for Abbott, Biosrnse Webster, Biotronik, Boston Sci, iRhythm, Field Medical, Pulse Bioselect and Medtronic. S. Khurshid receives sponsored research support from Bayer AG. All other authors declare no competing interests.

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Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases

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Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases

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