Nature Genetics

, volume 57 , issue 3 , pages 548-562

Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk

Seung Hoan Choi ^{1, 2}

Sean J. Jurgens ^{1, 3}

Ling Xiao ^{1, 4}

Matthew C. Hill ^{1, 4}

Christopher M Haggerty ⁵

Gardar Sveinbjörnsson ⁶

Valerie N. Morrill ¹

Nicholas A. Marston ^{7, 8}

Lu-Chen Weng ^{1, 4}

James Pirruccello ^{1, 4, 9}

David O. Arnar ^{6, 10, 11}

Daniel Fannar Gudbjartsson ^{6, 12}

Helene Mantineo ¹

Aenne S Von Falkenhausen ^{13, 14}

Andrea Natale ¹⁵

Arnljot Tveit ¹⁶

Bastiaan Geelhoed ¹⁷

Carolina Roselli ¹

David R. Van Wagoner ¹⁸

Dawood Darbar ¹⁹

Doreen Haase ²⁰

Elsayed Z. Soliman ²¹

Giovanni E. Davogustto ²²

Goo Jun ²³

Hugh Calkins ²⁴

Jeffrey L. Anderson ^{25, 26}

Jacob A. Brody ²⁷

Jennifer L. Halford ^{1, 4}

JOHN W. BARNARD ²⁸

John E Hokanson ²⁹

Jonathan D. Smith ¹⁸

Joshua C. Bis ²⁷

Kendra A. Young ²⁹

Linda S.B. Johnson ³⁰

L Risch ^{31, 32}

Lorne J. Gula ³³

Lydia Coulter Kwee ³⁴

M Chaffin ¹

M Kühne ³⁵

Michael Preuss ³⁶

Namrata Gupta ³⁷

Navid A. Nafissi ³⁸

Nicholas L. Smith ^{39, 40}

Peter M. Nilsson ^{41, 42}

Pim van der Harst ^{17, 43}

Quinn S. Wells ^{22, 44}

Renae L. Judy ^{45, 46}

Renate B. Schnabel ^{20, 47, 48}

Renee Johnson ^{49, 50}

Roelof A. J. Smit ³⁶

Stacey Gabriel ³⁷

Stacey Knight ^{25, 51}

Tetsushi Furukawa ⁵²

Thomas W. Blackwell ⁵³

Victor Nauffal ^{1, 4}

Xin Wang ^{1, 4}

Yuan-I Min ⁵⁴

Zachary T. Yoneda ²²

Zachary Laksman ⁵⁵

Connie R. Bezzina ³

Alvaro Alonso ⁵⁶

B Psaty ^{27, 39}

Christine M. Albert ⁵⁷

Dan E. Arking ⁵⁸

Dan M Roden ⁴⁴

Daniel I Chasman ^{37, 59}

Daniel J. Rader ⁶⁰

David Conen ⁶¹

David D McManus ⁶²

Diane Fatkin ^{49, 50, 63}

Emelia J. Benjamin ^{64, 65}

Eric Boerwinkle ⁶⁶

Gregory M. Marcus ⁹

Ingrid E. Christophersen ^{16, 67}

J. Gustav Smith ^{68, 69}

Jason D. Roberts ^{33, 70}

Laura M Raffield ⁷¹

Michael H. Cho ⁷²

Michael J Cutler ²⁵

Michiel Rienstra ¹⁷

Mina K. Chung ⁷³

Morten S. Olesen ^{74, 75}

Moritz F. Sinner ^{13, 14}

Nona Sotoodehnia ²⁷

Paulus Kirchhof ^{20, 47, 48, 76}

RUTH J. F. LOOS ^{36, 77}

Saman Nazarian ⁷⁸

SANGHAMITRA MOHANTY ^{15, 79}

Scott M. Damrauer ^{45, 46, 60}

Stefan Kääb ^{13, 14}

S R Heckbert ^{40, 80}

Susan Redline ⁸¹

Svati H. Shah ³⁸

Toshihiro Tanaka ^{82, 83}

Yusuke Ebana ⁸⁴

Goncalo Abecasis ^{6, 11}

Xiaodong Bai ^{7, 8}

Suganthi Balasubramanian ^{7, 8}

Aris Baras ^{2, 64}

Christina Beechert ^{1, 4, 85}

Boris Boutkov ^{1, 4, 85}

Hide authors affiliations Show authors affiliations: 85 affiliations

Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, USA |

Department of biostatistics, Boston University School of Public Health, Boston, USA |

Department of Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences (Heart Failure & Arrhythmias), Amsterdam UMC, Amsterdam, The Netherlands |

⁴

Cardiovascular Research Center, Massachsetts General Hospital, Harvard Medical School, Boston, USA |

⁵

Department of Translational Data Science and Informatics, Geisinger, Danville, USA |

⁶

deCODE genetics/AMGEN, Reykjavik, Iceland |

⁷

TIMI Study Group, Boston, USA |

⁸

Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA

Harvard University

Brigham and Women's Hospital

⁹

Division of Cardiology, University of California, San Francisco, San Francisco, USA |

¹⁰

Cardiovascular Center, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland |

¹¹

Faculty of medicine, University of Iceland, Reykjavik, Iceland |

¹²

Faculty of Electical and Computer Engineering and School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland |

¹³

Department of Medicine I, University Hospital Munich, Ludwig Maximilian University, Munich, Germany |

¹⁴

German Centre for Cardiovascular Research (DZHK), Partner site Munich Heart Alliance, Munich, Germany |

¹⁵

Texas Cardiac Arrhythmia Institute, St David’s Medical Center, Austin, USA |

¹⁶

Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Gjettum, Norway |

¹⁷

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands |

¹⁸

Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic, Cleveland, USA |

¹⁹

Division of Cardiology, University of Illinois at Chicago, Chicago, USA |

²⁰

Atrial Fibrillation Network (AFNET), Münster, Germany |

²¹

Epidemiological Cardiology Research Center (EPICARE), Department of Internal Medicine, Cardiology Section, Wake Forest School of Medicine, Winston-Salem, USA |

²²

Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, USA |

²³

Human Genetics Center, University of Texas Health Science Center at Houston, Houston, USA |

²⁴

Cardiac Arrhythmia Service, Johns Hopkins University School of Medicine, Baltimore, USA |

²⁵

Intermountain Heart Institute, Intermountain Medical Center, Murray, USA |

²⁶

Division of Cardiology, University of Utah, Salt Lake City, USA |

²⁷

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, USA |

²⁸

Departments of Quantitative Health Sciences, Cleveland Clinic, Cleveland, USA |

²⁹

Department of Epidemiology, University of Colorado, Anschutz Medical Campus, Aurora, USA |

³⁰

Department of Clinical Physiology, Department of Clinical Sciences, Skåne University Hospital and Lund University, Lund, Sweden |

³¹

Institute of Laboratory Medicine, Faculty of Medical Sciences, Private University of the Principality of Liechtenstein, Triesen, Liechtenstein |

³²

Center of Laboratory Medicine, University Institute of Clinical Chemistry, University of Bern, Inselspital, Bern, Switzerland |

³³

Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Canada |

³⁴

Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, USA |

³⁵

Cardiology/Electrophysiology, University Hospital Basel, University of Basel, Basel, Switzerland |

³⁶

The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, USA |

³⁷

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, USA |

³⁸

Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, USA |

³⁹

Department of Epidemiology, University of Washington, Seattle, USA |

⁴⁰

Kaiser Permanente Washington Health Research Institute, Seattle, USA |

⁴¹

Department of Clinical Sciences, Clinical Research Center, Lund University, Malmö, Sweden |

⁴²

Department of Internal medicine, Skåne University Hospital, Malmö, Sweden |

⁴³

Department of cardiology, University Medical Center Utrecht, Utrecht, The Netherlands |

⁴⁴

Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, USA |

⁴⁵

Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA |

⁴⁶

Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, USA |

⁴⁷

Department of Cardiology, University Heart and Vascular Center Hamburg, Hamburg, Germany |

⁴⁸

German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg/Kiel/Lübeck, Germany |

⁴⁹

Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Sydney, Australia |

⁵⁰

School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia |

⁵¹

Department of Medicine, University of Utah, Salt Lake City, USA |

⁵²

Department of Bio-Informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan |

⁵³

Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, USA |

⁵⁴

Department of Medicine, University of Mississippi Medical Center, Jackson, USA |

⁵⁵

Department of Medicine and the School of Biomedical Engineering, University of British Columbia, Vancouver, Canada |

⁵⁶

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, USA |

⁵⁷

Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, USA |

⁵⁸

McKusick–Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA |

⁵⁹

Divisions of Preventive Medicine and Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA

Harvard University

Brigham and Women's Hospital

⁶⁰

Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA |

⁶¹

Population health Research Institute, McMaster University, Hamilton, Canada |

⁶²

University of Massachusetts Chan Medical School Worcester, Worcester, USA |

⁶³

Cardiology Department, St. Vincent’s Hospital, Sydney, Australia |

⁶⁴

NHLBI and Boston University’s Framingham Heart Study, Framingham, USA

Boston University

National Heart, Lung, and Blood Institute

⁶⁵

Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, USA |

⁶⁶

Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, USA |

⁶⁷

Department of medical genetics, Oslo University Hospital, Oslo, Norway |

⁶⁸

Department of Cardiology, Lund University Diabetes Center and Wallenberg Center for Molecular Medicine, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden |

⁶⁹

The Wallenberg Laboratory/Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University and the Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden

University of Gothenburg

Sahlgrenska University Hospital

⁷⁰

Population Health Research Institute, McMaster University, and Hamilton Health Sciences, Hamilton, Canada

Hamilton Health Sciences

McMaster University

⁷¹

Department of Genetics, University of North Carolina At Chapel Hill, Chapel Hill, USA |

⁷²

Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, USA |

⁷³

Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, USA |

⁷⁴

Laboratory for Molecular Cardiology, Department of Cardiology, Centre for Cardiac, Vascular, Pulmonary and Infectious Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark |

⁷⁵

Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Copenhagen, Denmark |

⁷⁶

Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK |

⁷⁷

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

University of Copenhagen

Novo Nordisk

⁷⁸

Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, USA |

⁷⁹

Dell Medical School, Austin, USA |

⁸⁰

Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, USA |

⁸¹

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital, Boston, USA |

⁸²

Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University (TMDU) Graduate School of Medical and Dental Sciences, Tokyo, Japan |

⁸³

BioResource Research Center, Tokyo Medical and Dental University (TMDU), Tokyo, Japan |

⁸⁴

Life Science and Bioethics Research Center, Tokyo Medical and Dental University (TMDU), Tokyo, Japan |

⁸⁵

Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, USA |

Publication type: Journal Article

Publication date: 2025-03-06

Springer Nature

Nature Genetics

scimago Q1

wos Q1

SJR: 16.586

CiteScore: 45.1

Impact factor: 29.0

ISSN: 10614036, 15461718

DOI: 10.1038/s41588-025-02074-9

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Abstract

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia. Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

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Choi S. H. et al. Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk // Nature Genetics. 2025. Vol. 57. No. 3. pp. 548-562.

GOST all authors (up to 50) Copy

Choi S. H. et al. Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk // Nature Genetics. 2025. Vol. 57. No. 3. pp. 548-562.

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BibTex (up to 50 authors) Copy

@article{2025_Choi,

author = {Seung Hoan Choi and Sean J. Jurgens and Ling Xiao and Matthew C. Hill and Christopher M Haggerty and Gardar Sveinbjörnsson and Valerie N. Morrill and Nicholas A. Marston and Lu-Chen Weng and James Pirruccello and David O. Arnar and Daniel Fannar Gudbjartsson and Helene Mantineo and Aenne S Von Falkenhausen and Andrea Natale and Arnljot Tveit and Bastiaan Geelhoed and Carolina Roselli and David R. Van Wagoner and Dawood Darbar and Doreen Haase and Elsayed Z. Soliman and Giovanni E. Davogustto and Goo Jun and Hugh Calkins and Jeffrey L. Anderson and Jacob A. Brody and Jennifer L. Halford and JOHN W. BARNARD and John E Hokanson and Jonathan D. Smith and Joshua C. Bis and Kendra A. Young and Linda S.B. Johnson and L Risch and Lorne J. Gula and Lydia Coulter Kwee and M Chaffin and M Kühne and Michael Preuss and Namrata Gupta and Navid A. Nafissi and Nicholas L. Smith and Peter M. Nilsson and Pim van der Harst and Quinn S. Wells and Renae L. Judy and Renate B. Schnabel and Renee Johnson and Roelof A. J. Smit and others},

title = {Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk},

journal = {Nature Genetics},

year = {2025},

volume = {57},

publisher = {Springer Nature},

month = {mar},

url = {https://www.nature.com/articles/s41588-025-02074-9},

number = {3},

pages = {548--562},

doi = {10.1038/s41588-025-02074-9}

}

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Cite this

MLA Copy

Choi, Seung Hoan, et al. “Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.” Nature Genetics, vol. 57, no. 3, Mar. 2025, pp. 548-562. https://www.nature.com/articles/s41588-025-02074-9.

Publisher

Springer Nature

Journal

Nature Genetics

scimago Q1

wos Q1

SJR

16.586

CiteScore

45.1

Impact factor

29.0

ISSN

10614036 (Print)

15461718 (Electronic)

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