ArticleResearch square2026
Rare coding variant architecture and gene discovery from 130,000 sequenced cases of atrial fibrillation.
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109 authors.
Sean J JurgensCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0002-1605-9782
Nobuyuki EnzanCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0002-3899-4405
Ian R DinsmoreDepartment of Molecular and Functional Genomics, Geisinger Health System, Danville, PA, USA.
Seung Hoan ChoiDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Jon LuoDepartment of Molecular and Functional Genomics, Geisinger Health System, Danville, PA, USA.
Alex LipovDepartment of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands.
Cassandra HartleDepartment of Molecular and Functional Genomics, Geisinger Health System, Danville, PA, USA.
Xin WangCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0002-0322-8970
Nicholas A MarstonTIMI Study Group, Boston, MA, USA.ORCID 0000-0001-6164-4617
Lu-Chen WengCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0003-1475-4930
Giorgio Em MelloniTIMI Study Group, Boston, MA, USA.ORCID 0000-0001-6371-1334
Brandon ChalazanDepartment of Pediatrics, Division of Genetics, Genomics, and Metabolism, Lurie Children's Hospital of Chicago, Chicago, IL, USA.
Michael P GraySydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney.ORCID 0000-0003-1154-3011
James P PirruccelloDivision of Cardiology, University of California San Francisco, San Francisco, CA, USA.ORCID 0000-0001-6088-4037
Annette DiazCollege of Liberal Arts and Sciences, University of Illinois Chicago, Chicago, IL, USA.
Mark D ChaffinCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0002-1234-5562
Aylin Ornelas-LoredoDivision of Cardiology, University of Illinois Chicago, Chicago, IL, USA.
Owen TangCardiovascular Discovery Group, Kolling Institute of Medical Research, St Leonards, New South Wales, Australia.
Faisal A DarbarDepartment of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Shinwan KanyCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Yining ChenDepartment of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Aenne S von FalkenhausenDepartment of Medicine I, University Hospital Munich, Ludwig-Maximilians-University, Munich, Germany.ORCID 0000-0001-9453-3016
Alanna C MorrisonHuman Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.ORCID 0000-0001-6381-4296
Andrea NataleTexas Cardiac Arrhythmia Institute, St David's Medical Center, Austin, TX, USA.
Arnljot TveitDepartment of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Gjettum, Norway.
Bastiaan GeelhoedDepartment of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
Brian CadeDivision of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA.ORCID 0000-0003-1424-0673
David R Van WagonerDepartment of Cardiovascular & Metabolic Sciences, Cleveland Clinic, Cleveland, OH, USA.ORCID 0000-0001-8250-9828
Doreen HaaseAtrial Fibrillation NETwork (AFNET), Münster, Germany.
Elsayed Z SolimanDepartment of Internal Medicine, Cardiology Section, Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, NC, USA.ORCID 0000-0001-5632-8150
Giovanni E DavogusttoDepartment of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Hugh CalkinsDepartment of Medicine, Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Jeffrey L AndersonIntermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA.
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.ORCID 0000-0001-8509-148X
John BarnardDepartments of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA.ORCID 0000-0003-2403-8268
John E HokansonAnschutz Medical Campus, Department of Epidemiology, University of Colorado, Aurora, CO, USA.
Jonathan D SmithDepartment of Cardiovascular & Metabolic Sciences, Cleveland Clinic, Cleveland, OH, USA.ORCID 0000-0002-0415-386X
Joshua C BisCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.ORCID 0000-0002-3409-1110
Kendra YoungAnschutz Medical Campus, Department of Epidemiology, University of Colorado, Aurora, CO, USA.ORCID 0000-0002-8664-7635
Linda Sb JohnsonDepartment of Clinical Physiology, Department of Clinical Sciences, Skåne University Hospital and Lund University, Lund, Sweden.ORCID 0000-0002-2249-8220
Leann LongDepartment of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Lorenz RischInstitute of Laboratory Medicine, Faculty of Medical Sciences, Private University of the Principality of Liechtenstein, Triesen, Liechtenstein.ORCID 0000-0003-2692-6699
Lorne J GulaSection of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada.
Lydia Coulter KweeDuke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.ORCID 0000-0002-6997-8571
Michael KühneCardiology/Electrophysiology, University Hospital Basel, University of Basel, Basel, Switzerland.ORCID 0000-0002-2937-3711
Michael PreussThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0001-5266-8465
Namrata GuptaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Navid A NafissiDivision of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.ORCID 0000-0003-0706-9548
Nicholas L SmithDepartment of Epidemiology, University of Washington, Seattle, WA, USA.ORCID 0000-0003-3483-353X
Peter M NilssonDepartment of Clinical Sciences, Clinical Research Center, Lund University, Malmö, Sweden.ORCID 0000-0002-5652-8459
Pim van der HarstDepartment of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
Quinn S WellsDepartment of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.ORCID 0009-0009-4141-1520
Renae L JudyDepartment of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Renate B SchnabelAtrial Fibrillation NETwork (AFNET), Münster, Germany.ORCID 0000-0001-7170-9509
Renee JohnsonMolecular Cardiology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
Roelof Aj SmitThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0001-9822-6726
Stacey GabrielProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stacey KnightIntermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA.ORCID 0000-0003-0092-7327
Tetsushi FurukawaDepartment of Bio-Informational Pharmacology, Medical Research Institute, Institute of Science Tokyo, Tokyo, Japan.
Yuan-I MinDepartment of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.ORCID 0000-0003-2470-0004
Zachary T YonedaDepartment of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Zachary Wm LaksmanDepartment of Medicine and the School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.ORCID 0000-0002-7790-541X
Alvaro AlonsoDepartment of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.ORCID 0000-0002-2225-8323
Bruce M PsatyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Christine M AlbertDepartment of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA.ORCID 0000-0002-2081-1121
Dan E ArkingMcKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID 0000-0001-8980-8695
Dan M RodenDepartments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.ORCID 0000-0002-6302-0389
Daniel I ChasmanProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0003-3357-0862
Daniel J RaderDivision of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0002-9245-9876
David ConenPopulation Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
David D McManusUniversity of Massachusetts Chan Medical School Worcester, Worcester, MA, USA.
Diane FatkinMolecular Cardiology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.ORCID 0000-0002-9010-9856
Eric BoerwinkleHuman Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Gregory M MarcusDivision of Cardiology, University of California San Francisco, San Francisco, CA, USA.ORCID 0000-0001-5197-7696
Ingrid E ChristophersenDepartment of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Gjettum, Norway.
J Gustav SmithDepartment of Cardiology, Lund University Diabetes Center and Wallenberg Center for Molecular Medicine and Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
Jason D RobertsSection of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada.
Laura M RaffieldDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
M Benjamin ShoemakerDepartment of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Michael H ChoChanning Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Michael J CutlerIntermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA.ORCID 0000-0001-9498-7472
Mina K ChungDepartment of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA.
Morten S OlesenLaboratory for Molecular Cardiology, Department of Cardiology, Centre for Cardiac, Vascular, Pulmonary and Infectious Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Moritz F SinnerDepartment of Medicine I, University Hospital Munich, Ludwig-Maximilians-University, Munich, Germany.ORCID 0000-0002-6660-796X
Nona SotoodehniaCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Paulus KirchhofAtrial Fibrillation NETwork (AFNET), Münster, Germany.ORCID 0000-0002-1881-0197
Ruth Jf LoosThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Saman NazarianDivision of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Sanghamitra MohantyTexas Cardiac Arrhythmia Institute, St David's Medical Center, Austin, TX, USA.ORCID 0000-0001-6601-944X
Scott M DamrauerDepartment of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.ORCID 0000-0001-8009-1632
Stefan KaabDepartment of Medicine I, University Hospital Munich, Ludwig-Maximilians-University, Munich, Germany.ORCID 0000-0001-8824-3581
Susan R HeckbertKaiser Permanente Washington Health Research Institute, Seattle, WA, USA.ORCID 0000-0002-7100-512X
Susan RedlineDivision of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA.ORCID 0000-0002-6585-1610
Svati H ShahDivision of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
Toshihiro TanakaDepartment of Human Genetics and Disease Diversity and BioResource Research Center, Institute of Science Tokyo Graduate School of Medical and Dental Sciences, Tokyo, Japan.ORCID 0000-0001-6201-9784
Yusuke EbanaLife Science and Bioethics Research Center, Institute of Science Tokyo, Tokyo, Japan.ORCID 0000-0002-5162-0838
Regeneron Genetics Center
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Steven A LubitzDemoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA.ORCID 0000-0002-9599-4866
Kathryn L LunettaDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.ORCID 0000-0002-9268-810X
Emelia J BenjaminDepartment of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA, USA.ORCID 0000-0003-4076-2336
Michiel RienstraDepartment of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.ORCID 0000-0002-2581-070X
Gemma A FigtreeDepartment of Cardiology, Royal North Shore Hospital, Sydney, New South Wales, Australia.
Dawood DarbarDivision of Cardiology, University of Illinois Chicago, Chicago, IL, USA.ORCID 0000-0002-4103-5977
Connie R BezzinaDepartment of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands.ORCID 0000-0002-0633-3514
Christian T RuffTIMI Study Group, Boston, MA, USA.
Marc S SabatineTIMI Study Group, Boston, MA, USA.
Tooraj MirshahiDepartment of Molecular and Functional Genomics, Geisinger Health System, Danville, PA, USA.ORCID 0000-0002-0754-3820
Patrick T EllinorCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Funding
IDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVALR01HL092577 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI BENJAMIN, EMELIA J., ELLINOR, PATRICK THOMAS · 2009 to 2025
$20.6MProject 3 Genes to Omics-Informed Drugs: Drug Repositioning and Testing to Prevent AF ProgressionsP01HL158502 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI Robert Alden Koeth · 2022 to 2026
$16.9MFunctional Genomics of Atrial Fibrillation in Human AtriaR01HL111314 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI BARNARD, JOHN, CHUNG, MINA KAY · 2012 to 2019
$6.1MGenetics of Atrial FibrillationR01HL090620 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI BARNARD, JOHN, CHUNG, MINA KAY · 2008 to 2012
$2.9MUsing Electrocardiogram Genetics to Inform Arrhythmia RiskR01HL157635 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI ELLINOR, PATRICK THOMAS, MIRSHAHI, TOORAJ · 2022 to 2025
$2.9MInfrastructure for mentored access to CHS data and specimensR01HL172803 · NHLBI · UNIVERSITY OF WASHINGTON · PI James S Floyd, Michelle Christina Odden · 2025 to 2026
$2.7MMentoring in Arrhythmia ResearchK24HL105780 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI ELLINOR, PATRICK THOMAS · 2011 to 2020
$1.2MNHLBI NIH HHS K24 HL105780NHLBI NIH HHS P01 HL158502NHLBI NIH HHS R01 HL090620NHLBI NIH HHS R01 HL092577NHLBI NIH HHS R01 HL111314NHLBI NIH HHS R01 HL157635NHLBI NIH HHS R01 HL172803
Abstract
Rare coding genetic variants may exert large effects on risk of common disease, yet their contribution to disease architecture and their utility in gene prioritization remain limited by inadequate sample sizes. Here, we performed a massive-scale rare variant association study (RVAS), analyzing over 1.1 million sequenced participants among which 130,000 had atrial fibrillation (AF). Through a multi-mask burden testing approach, we identified 15 genes significantly associated with AF through rare large-effect variation. Integrative analyses revealed strong convergence between genes implicated by rare and common variation, and highlighted instances where RVAS data may aid in GWAS prioritization. Nevertheless, several RVAS genes were not among GWAS loci (
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