Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy
Rafik Tadros, Sean L. Zheng, Christopher Grace, Paloma Jordà, Catherine Francis, Dominique M West, Sean J. Jurgens, Kate Thomson, Andrew R. Harper, Elizabeth Ormondroyd, Xiao Yun Xu, Pantazis Theotokis, Rachel Buchan, Kathryn A. McGurk, Francesco Mazzarotto, Beatrice Boschi, Elisabetta Pelo, Michael Lee, Michela Noseda, Amanda Varnava, Alexa M.C. Vermeer, Roddy Walsh, Ahmad S. Amin, Marjon A. van Slegtenhorst, Nicole M. Roslin, Lisa J. Strug, Erika Salvi, Chiara Lanzani, Antonio de Marvao, Hypergenes InterOmics Collaborators, Daniele Cusi, Paolo Manunta, Lorena Citterio, Nicola Glorioso, Jason D. Roberts, Maxime Tremblay‐Gravel, Geneviève Giraldeau, Julia Cadrin‐Tourigny, Philippe L. L’Allier, Patrick Garceau, Mario Talajic, Sarah A. Gagliano Taliun, Yigal M. Pinto, Harry Rakowski, Antonis Pantazis, Wenjia Bai, John Baksi, Brian P. Halliday, Sanjay Prasad, Paul J.R. Barton, Declan P. O’Regan, Stuart A. Cook, Rudolf A. de Boer, Imke Christiaans, Michelle Michels, Christopher M. Kramer, Carolyn Y. Ho, Stefan Neubauer, HCMR Investigators, Theodore Abraham, Lisa Anderson, Florian Andre, Evan Appelbaum, Camillo Autore, Lauren Baldassarre, Colin Berry, Elena Biagini, William Bradlow, Chiara Bucciarelli-Ducci, Amedeo Chiribiri, Lubna Choudhury, Andrew Crean, Dana Dawson, Milind Desai, Patrice Desvigne-Nickens, John DiMarco, Eleanor Elstein, Andrew Flett, Matthias Friedrich, Eli Gelfand, Nancy Geller, Tjeerd Germans, Jeffrey Geske, Allison Hays, Stephen B. Heitner, Adam Helms, Daniel Jacoby, Dong-Yun Kim, Bette Kim, Han Kim, Paul Kolm, Raymond Kwong, Eric Larose, Christopher Madias, Masliza Mahmod, Heiko Mahrholdt, Martin Maron, Ahmad Masri, Gerry McCann, Saidi Mohiddin
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.