Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management.

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Publication Details

Journal
Nature Genetics
Published
2025-02-18
DOI
https://doi.org/10.1038/s41588-025-02087-4
Citations
43
Primary Topic
Cardiomyopathy and Myosin Studies
Type
article
Field-Weighted Citation Impact
59.69

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article

Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy

Maxime Tremblay‐Gravel, Carolyn Yung Ho, Arthur A.M. Wilde, Arnon Adler et al.
43 citations
Nature Genetics
Cardiomyopathy and Myosin Studies
59.69
article

Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy

Maxime Tremblay‐Gravel, Carolyn Yung Ho, Arthur A.M. Wilde, Arnon Adler, Mario Talajic, Jason D. Roberts, Connie R. Bezzina, Michelle Michels, James S. Ware, Dominique M West, Amanda Varnava, Elisabetta Pelo, Rafik Tadros, Paul J.R. Barton, Iacopo Olivotto, Nicole M. Roslin, Catherine Francis, Sean L. Zheng, Rudolf A. de Boer, Chiara Lanzani, Pantazis Theotokis, Alexa M.C. Vermeer, Hugh Watkins, Rachel Buchan, Brian P. Halliday, Kate Thomson, Christopher M. Kramer, Lisa J. Strug, Elizabeth Ormondroyd, Andrew R. Harper, Ahmad S. Amin, Imke Christiaans, Jean‐Claude Tardif, Michela Noseda, Geneviève Giraldeau, Roddy Walsh, Patrick Garceau, Xiao Yun Xu, Erika Salvi, Anuj Goel, Wenjia Bai, Yigal M. Pinto, Sarah A. Gagliano Taliun, Sanjay Prasad, Christopher Grace, Julia Cadrin‐Tourigny, Paul M. Matthews, Marjon A. van Slegtenhorst, Stuart A. Cook, Antonio de Marvao, Francesco Mazzarotto, Stefan Neubauer, Beatrice Boschi, Kathryn A. McGurk, Sean J. Jurgens, Paloma Jordà, Michael Lee, Antonis Pantazis, Harry Rakowski, John Baksi
article en
43 citations

Abstract

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management.

Nature GeneticsVol. 57(3)
Broad Institute (US), Northwestern University (US), Western University (CA), Brigham and Women's Hospital (US), Tufts Medical Center (US), Houston Methodist (US), University of Leeds (GB), Beth Israel Deaconess Medical Center (US), Cleveland Clinic (US), University Health Network (CA), University Medical Center Groningen (NL), Johns Hopkins University (US), Imperial College Healthcare NHS Trust (GB), University of Leicester (GB), Vita-Salute San Raffaele University (IT), University of Sassari (IT), Oregon Health & Science University (US), St George's, University of London (GB), National University of Singapore (SG), University of Calgary (CA), University of Groningen (NL), Duke University (US), King's College London (GB), University of Toronto (CA), University of Aberdeen (GB), Guy's and St Thomas' NHS Foundation Trust (GB), Cornell University (US), Heidelberg University (DE), University of Michigan (US), Royal Brompton & Harefield NHS Foundation Trust (GB), Montreal Heart Institute (CA), Churchill Hospital (GB), Hospital for Sick Children (CA), Erasmus MC (NL), University Hospital Heidelberg (DE), John Radcliffe Hospital (GB), Robert Bosch Hospital (DE), Harefield Hospital (GB), University Hospital Southampton NHS Foundation Trust (GB), British Heart Foundation (GB), Yale University (US), University of Bristol (GB), University of Oxford (GB), NYU Langone Health (US), Lung Institute (US), National Heart, Lung, and Blood Institute (US), Amsterdam Neuroscience (NL), NIHR Imperial Biomedical Research Centre (GB), Construction Technologies Institute (IT), Meyer Children's Hospital (IT), Azienda Ospedaliero-Universitaria Careggi (IT), Mayo Clinic in Arizona (US), Public Health Ontario (CA), UK Dementia Research Institute (GB), IRCCS Ospedale San Raffaele (IT), NIHR Surgical Reconstruction and Microbiology Research Centre (GB), ERN GUARD-Heart (NL), Oxford BioMedica (United Kingdom) (GB), National Heart Centre Singapore (SG), Biogen (Switzerland) (CH), Amsterdam University Medical Centers (NL), Istituti di Ricovero e Cura a Carattere Scientifico (IT), National Research Council (IT), MRC London Institute of Medical Sciences (GB), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Weill Cornell Medicine (US), Imperial College London (GB), McGill University (CA), University of Virginia (US), Amsterdam University of Applied Sciences (NL), Libin Cardiovascular Institute of Alberta (CA), Université de Montréal (CA), Charité - Universitätsmedizin Berlin (DE), University of Glasgow (GB), University of Pennsylvania (US), University of Brescia (IT), Sapienza University of Rome (IT), Vrije Universiteit Amsterdam (NL), MedStar Health (US), University of Amsterdam (NL), University of Bologna (IT), University of Edinburgh (GB), Icahn School of Medicine at Mount Sinai (US)
Israel Cancer Research Fund, Wellcome Trust, Deutsches Zentrum für Herz-Kreislaufforschung, Maudsley Charity, Alzheimer's Society, Amsterdam University Medical Centers, Cancer Research UK, National Institute for Health and Care Research, British Heart Foundation, Department of Health and Social Care, Imperial College London, King's College London, European Commission, Fondation Leducq, ZonMw, Fetal Medicine Foundation, Novo Nordisk, Novo Nordisk Fonden, Fondation Institut de Cardiologie de Montréal, Institut de Cardiologie de Montréal, UK Dementia Research Institute, National Institutes of Health, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Canadian Institutes of Health Research, Medical Research Council, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of Neurological Disorders and Stroke, Common Fund
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