Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy
Authors: Tadros Rafik , Zheng Sean L. , Grace Christopher , Jordà Paloma , Francis Catherine , West Dominique M. , Jurgens Sean J. , Thomson Kate L. , Harper Andrew R. , Ormondroyd Elizabeth , Xu Xiao , Theotokis Pantazis I. , Buchan Rachel J. , McGurk Kathryn A. , Mazzarotto Francesco , Boschi Beatrice , Pelo Elisabetta , Lee Michael , Noseda Michela , Varnava Amanda , Vermeer Alexa M. C. , Walsh Roddy , Amin Ahmad S. , van Slegtenhorst Marjon A. , Roslin Nicole M. , Strug Lisa J. , Salvi Erika , Lanzani Chiara , de Marvao Antonio ,   Hypergenes InterOmics Collaborators, Cusi Daniele , Manunta Paolo , Citterio Lorena , Glorioso Nicola , Roberts Jason D. , Tremblay-Gravel Maxime , Giraldeau Genevieve , Cadrin-Tourigny Julia , L’Allier Philippe L. , Garceau Patrick , Talajic Mario , Gagliano Taliun Sarah A. , Pinto Yigal M. , Rakowski Harry , Pantazis Antonis , Bai Wenjia , Baksi John , Halliday Brian P. , Prasad Sanjay K. , Barton Paul J. R. , O’Regan Declan P. , Cook Stuart A. , de Boer Rudolf A. , Christiaans Imke , Michels Michelle , Kramer Christopher M. , Ho Carolyn Y. , Neubauer Stefan ,   HCMR Investigators, Abraham Theodore , Anderson Lisa , Andre Florian , Appelbaum Evan , Autore Camillo , Baldassarre Lauren , Berry Colin , Biagini Elena , Bradlow William , Bucciarelli-Ducci Chiara , Chiribiri Amedeo , Choudhury Lubna , Crean Andrew , Dawson Dana , Desai Milind , Desvigne-Nickens Patrice , DiMarco John , Elstein Eleanor , Flett Andrew , Friedrich Matthias , Gelfand Eli , Geller Nancy , Germans Tjeerd , Geske Jeffrey , Hays Allison , Heitner Stephen B. , Helms Adam , Jacoby Daniel , Kim Dong-Yun , Kim Bette , Kim Han , Kolm Paul , Kwong Raymond , Larose Eric , Madias Christopher , Mahmod Masliza , Mahrholdt Heiko , Maron Martin , Masri Ahmad , McCann Gerry , Mohiddin Saidi , Mongeon Francois-Pierre , Nagueh Sherif , Newby David , Nightingale Angus , Owens Anjali , Plein Sven , Raman Betty , Rimoldi Ornella , Salerno Michael , Schulz-Menger Jeanette , Sharma Sanjay , Sherrid Mark , van Rossum Albert , Weinsaft Jonathan , Weintraub William , White James , Williamson Eric , Woo Anna , Matthews Paul M. , Wilde Arthur A. M. , Tardif Jean-Claude , Olivotto Iacopo , Adler Arnon , Goel Anuj , Ware James S. , Bezzina Connie R. , Watkins Hugh 
Published: February 2025

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.