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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,\n                    <jats:italic>SVIL<\/jats:italic>\n                    , which encodes the actin-binding protein supervillin, showing that rare truncating\n                    <jats:italic>SVIL<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41588-025-02087-4","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T05:03:06Z","timestamp":1739854986000},"page":"530-538","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy"],"prefix":"10.1038","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1472-0258","authenticated-orcid":false,"given":"Rafik","family":"Tadros","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5762-6392","authenticated-orcid":false,"given":"Sean L.","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Grace","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9236-1713","authenticated-orcid":false,"given":"Paloma","family":"Jord\u00e0","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Francis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique M.","family":"West","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1605-9782","authenticated-orcid":false,"given":"Sean J.","family":"Jurgens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2807-3431","authenticated-orcid":false,"given":"Kate L.","family":"Thomson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5327-0328","authenticated-orcid":false,"given":"Andrew R.","family":"Harper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9116-4064","authenticated-orcid":false,"given":"Elizabeth","family":"Ormondroyd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8718-230X","authenticated-orcid":false,"given":"Pantazis I.","family":"Theotokis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2490-9289","authenticated-orcid":false,"given":"Rachel J.","family":"Buchan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5445-6906","authenticated-orcid":false,"given":"Kathryn A.","family":"McGurk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6159-9980","authenticated-orcid":false,"given":"Francesco","family":"Mazzarotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Boschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Pelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0186-4439","authenticated-orcid":false,"given":"Michael","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9553-5029","authenticated-orcid":false,"given":"Michela","family":"Noseda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Varnava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa M. 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A.R.H. is a current employee and stockholder of AstraZeneca. D.P.O. has received grants and consultancy fees from Bayer. R.d.B. has received research grants and\/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc., Novo Nordisk and Roche, and also has speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis and Roche. P.G. receives research funds from Abbott Cardiovascular and Medtronics. M.M. has received research support or consultancy fees from Bristol Myers Squibb, Cytokinetics, Pfizer, Sanofi Genzyme, Biomarin and Alnylam. C.M.K. received research grants from Cytokinetics and Bristol Myers Squibb. P.M.M. has received consultancy fees from Roche, Biogen, Nodthera and Sangamo Pharmaceuticals and has received research or educational funds from Biogen, Novartis, Merck and Bristol Myers Squibb. J.-C.T. has received research grants from Amarin, AstraZeneca, Ceapro, DalCor, Esperion, Ionis, Novartis, Pfizer and RegenXBio; honoraria from AstraZeneca, DalCor, HLS Therapeutics, Pendopharm and Pfizer; holds minor equity interest in DalCor; and is an author of a patent on pharmacogenomics-guided CETP inhibition. J.S.W. has received research support or consultancy fees from Myokardia, Bristol Myers Squibb, Pfizer and Foresite Labs. C.R.B. has consulted for Illumina. H.W. has consulted for Cytokinetics, BridgeBio and BioMarin. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}