ArticleNature genetics2025
Common-variant and rare-variant genetic architecture of heart failure across the allele-frequency spectrum.
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Article in Nature genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 27 papers, 1 of them a synthesis that pooled it.
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27citing papers in PubMed, 1 pooled it
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Who cites it
27 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Multi-ancestry genetic architecture of heart failure subtypes.Nature communications · 2026Pooled it
- Convergent coexpression reveals shared biological mechanisms underlying common and rare variant risk in six neuropsychiatric disorders.Molecular psychiatry · 2026Article
- Heart failure with mildly reduced ejection fraction (HFmrEF): where are we now?Heart failure reviews · 2026Review
- When splicing is not all or none: GT>GC 5' splice-site variants as a model for intermediate effects and challenges in variant classification.HGG advances · 2026Article
- Preserved ratio impaired spirometry, plasma proteomics, and incident heart failure.Journal of advanced research · 2026Article
- Bridging ancestry gaps in genomic risk prediction with tabular foundation models.Bioinformatics (Oxford, England) · 2026Article
- Cardiovascular Genetic Epidemiology in the Genome-Wide Era: From Association Discovery to Mechanistic Dissection and Clinical Translation.Cardiovascular drugs and therapy · 2026Review
- Bridging Ancestry Gaps in Genomic Risk Prediction with Tabular Foundation Models.bioRxiv : the preprint server for biology · 2026Article
- Body Mass Index, Clinical Outcomes, and Mortality in Heart Failure: A Mendelian Randomization Study.Journal of the American College of Cardiology · 2026Article
- Genetic perspectives on the comorbidity of anxiety and mood disorders with cardiovascular disease.Nature cardiovascular research · 2026Review
- Prostate Cancer, Genetic Susceptibility, and Risk of Chronic Non-Urological Complications.The Prostate · 2026Article
- Molecular Mechanisms and Multi-Omics Integration in Heart Failure: From Pathophysiology to Precision Medicine.International journal of molecular sciences · 2026Review
- Genetic determinants of heart failure susceptibility and response in the collaborative cross mouse population.Genetics · 2026Article
- Genetic factors contributing to atherosclerosis.Current opinion in cardiology · 2026Review
- Combinatorial effects of gene dosage, polygenic background and environment on complex traits.medRxiv : the preprint server for health sciences · 2026Article
- Molecular systems, human noncoding sequence variants, and blood pressure.Physiological reviews · 2026Review
- Polygenic Background and Penetrance of Pathogenic Variants in Hypertrophic and Dilated Cardiomyopathies.JAMA cardiology · 2026Article
- Integrating Polygenic Scores with Clinical, Lifestyle, and Social Risk Factors to Improve Heart Failure Risk Prediction.Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing · 2026Article
- Alpha-7 nicotinic acetylcholine receptor: targeting the interplay between inflammation, renin-angiotensin aldosterone system, and nervous system for the novel treatment of heart failure.Frontiers in pharmacology · 2026Review
- Heart Failure With Mildly Reduced Ejection Fraction: A Call for a Precision Medicine Approach.JACC. Advances · 2026Review
Corrections and comments
- Erratum issued
- Update of
Authors and funding
36 authors.
David S M LeeDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.ORCID http://orcid.org/0000-0002-8821-9028
Kathleen M CardoneDepartment of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
David Y ZhangDepartment of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-1377-9829
Noah L TsaoDepartment of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-5743-0795
Sarah AbramowitzDepartment of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0001-5515-1752
Pranav SharmaDepartment of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
John S DePaoloDepartment of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Mitchell ConeryGenomics and Computational Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0001-7640-0797
Krishna G AragamCenter for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-3223-9131
Kiran BiddingerProgram in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Ozan DikilitasDepartment of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.ORCID http://orcid.org/0000-0002-9906-8608
Lily Hoffman-AndrewsDivision of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0001-8021-8306
Renae L JudyDepartment of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Atlas KhanDivision of Nephrology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York City, NY, USA.ORCID http://orcid.org/0000-0002-6651-2725
Iftikhar J KulloDepartment of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.ORCID http://orcid.org/0000-0002-6524-3471
Megan J PuckelwartzDepartment of Pharmacology, Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.ORCID http://orcid.org/0000-0002-0455-2983
Nosheen RezaDivision of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Benjamin A SatterfieldDepartment of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
Pankhuri SinghalDepartment of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Penn Medicine Biobank
Zoltan AranyDivision of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-1368-2453
Thomas P CappolaDivision of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Eric D CarruthDepartment of Genomic Health, Geisinger, Danville, PA, USA.ORCID http://orcid.org/0000-0001-8184-8676
Sharlene M DayDivision of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Ron DoThe Charles Bronfman Institute for Personalized Medicine, Mount Sinai Icahn School of Medicine, New York City, NY, USA.ORCID http://orcid.org/0000-0002-3144-3627
Christopher M HaggertyDepartment of Translational Data Science and Informatics, Geisinger, Danville, PA, USA.
Jacob JosephDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Elizabeth M McNallyCenter for Genetic Medicine, Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.ORCID http://orcid.org/0000-0002-1221-719X
Girish NadkarniDivision of Nephrology, Department of Medicine, Mount Sinai Icahn School of Medicine, New York City, NY, USA.ORCID http://orcid.org/0000-0001-6319-4314
Anjali T OwensCardiovascular Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Daniel J RaderDepartment of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-9245-9876
Marylyn D RitchieDepartment of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-1208-1720
Yan V SunAtlanta VA Health Care System, Decatur, GA, USA.ORCID http://orcid.org/0000-0002-2838-1824
Benjamin F VoightDepartment of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-6205-9994
Michael G Levin *Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. michael.levin@pennmedicine.upenn.edu.ORCID http://orcid.org/0000-0002-9937-9932
Scott M Damrauer *Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0001-8009-1632
Funding
Technology to Empower Changes in Health (TECH) Network Participant Technologies CenterU24OD023176 · OD · SCRIPPS RESEARCH INSTITUTE, THE · PI TOPOL, ERIC JEFFREY · 2016 to 2022
$204.7MPrecision Medicine Initiative Cohort Program BiobankU24OD023121 · OD · MAYO CLINIC ROCHESTER · PI CEKANOVA, MARIA, CICEK, MINE · 2016 to 2024
$185.5MEnhancing All of Us Data Resources for Nutrition Precision Health: the All of Us Data and Research CenterU2COD023196 · OD · VANDERBILT UNIVERSITY MEDICAL CENTER · PI GLAZER, DAVID, HARRIS, PAUL A. · 2016 to 2022
$143.7MAdaptive Platform for Personalized EngagementU24OD023163 · OD · VIGNET, INC. · PI JAIN, PRADUMAN · 2017 to 2020
$102.6MPhenotypic Diversity in COVID-19UL1TR001878 · NCATS · UNIVERSITY OF PENNSYLVANIA · PI FITZGERALD, GARRET A · 2016 to 2025
$102.4MUniversity of Arizona-Banner Health All of Us Research Program OT2OD026549 · OD · UNIVERSITY OF ARIZONA · PI MORENO, FRANCISCO A, REIMAN, ERIC MICHAEL · 2018 to 2023
$78.9MCalifornia Precision Medicine Research Program ConsortiumOT2OD026552 · OD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ANTON-CULVER, HODA A, OHNO-MACHADO, LUCILA · 2018 to 2023
$73.4MAll of Us PennsylvaniaOT2OD026554 · OD · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI REIS, STEVEN E, VISWESWARAN, SHYAM · 2018 to 2023
$72.1MNew York City Consortium for Precision MedicineOT2OD026556 · OD · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BIER, LOUISE E, GHARAVI, ALI G · 2018 to 2023
$67.3MSouthEast Enrollment Center (SEEC) OT2OD026551 · OD · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI CARRASQUILLO, OLVEEN, COLON, VIVIAN · 2018 to 2023
$62.8MSouthern All of Us NetworkOT2OD026548 · OD · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI FOUAD, MONA N., KORF, BRUCE R · 2018 to 2023
$60.5MIllinois Precision Medicine Consortium OT2OD026557 · OD · NORTHWESTERN UNIVERSITY AT CHICAGO · PI AHSAN, HABIBUL, ARGOS, MARIA · 2018 to 2023
$60.5MBLRD VA IK2 BX006551CSRD VA IK2 CX001780NCATS NIH HHS UL1 TR001878NHLBI NIH HHS F30 HL172382NHLBI NIH HHS K23 HL166961NHLBI NIH HHS R01 HL168841NHLBI NIH HHS R01 HL169458NHLBI NIH HHS T32 HL007843NIDDK NIH HHS R01 DK134575NIDDK NIH HHS UM1 DK126194NIGMS NIH HHS T32 GM007170NIH HHS OT2 OD023205NIH HHS OT2 OD023206NIH HHS OT2 OD025276NIH HHS OT2 OD025277NIH HHS OT2 OD025315NIH HHS OT2 OD025337NIH HHS OT2 OD026548NIH HHS OT2 OD026549NIH HHS OT2 OD026550NIH HHS OT2 OD026551NIH HHS OT2 OD026552NIH HHS OT2 OD026553NIH HHS OT2 OD026554NIH HHS OT2 OD026555NIH HHS OT2 OD026556NIH HHS OT2 OD026557NIH HHS U24 OD023121NIH HHS U24 OD023163NIH HHS U24 OD023176NIH HHS U2C OD023196U.S. Department of Health & Human Services | National Institutes of Health (NIH) DK126194U.S. Department of Health & Human Services | National Institutes of Health (NIH) DK134575U.S. Department of Health & Human Services | National Institutes of Health (NIH) F30HL172382U.S. Department of Health & Human Services | National Institutes of Health (NIH) HL168841U.S. Department of Health & Human Services | National Institutes of Health (NIH) HL169458U.S. Department of Health & Human Services | National Institutes of Health (NIH) T32GM007170U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) K23HL166961U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) T32HL007843U.S. Department of Veterans Affairs (Department of Veterans Affairs) IK2-BX006551U.S. Department of Veterans Affairs (Department of Veterans Affairs) IK2-CX001780
Abstract
Heart failure is a complex trait, influenced by environmental and genetic factors, affecting over 30 million individuals worldwide. Here we report common-variant and rare-variant association studies of all-cause heart failure and examine how different classes of genetic variation impact its heritability. We identify 176 common-variant risk loci at genome-wide significance in 2,358,556 individuals and cluster these signals into five broad modules based on pleiotropic associations with anthropomorphic traits/obesity, blood pressure/renal function, atherosclerosis/lipids, immune activity and arrhythmias. In parallel, we uncover exome-wide significant associations for heart failure and rare predicted loss-of-function variants in TTN, MYBPC3, FLNC and BAG3 using exome sequencing of 376,334 individuals. We find that total burden heritability of rare coding variants is highly concentrated in a small set of Mendelian cardiomyopathy genes, while common-variant heritability is diffusely spread throughout the genome. Finally, we show that common-variant background modifies heart failure risk among carriers of rare pathogenic truncating variants in TTN. Together, these findings discern genetic links between dysregulated metabolism and heart failure and highlight a polygenic component to heart failure not captured by current clinical genetic testing.
Indexed as
Gene FrequencyGenetic Predisposition to DiseaseGenetic VariationHeart FailureAdaptor Proteins, Signal TransducingApoptosis Regulatory ProteinsCarrier ProteinsConnectinExome SequencingFemaleGenome-Wide Association StudyHumansMaleMyosin Binding Protein CPolymorphism, Single NucleotideAdaptor Proteins, Signal TransducingApoptosis Regulatory ProteinsBAG3 protein, humanCarrier ProteinsConnectinMyosin Binding Protein CTTN protein, human
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