Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy.
Tadros R., Zheng SL., Grace C., Jordà P., Francis C., West DM., Jurgens SJ., Thomson KL., Harper AR., Ormondroyd E., Xu X., Theotokis PI., Buchan RJ., McGurk KA., Mazzarotto F., Boschi B., Pelo E., Lee M., Noseda M., Varnava A., Vermeer AMC., Walsh R., Amin AS., van Slegtenhorst MA., Roslin NM., Strug LJ., Salvi E., Lanzani C., de Marvao A., Hypergenes InterOmics Collaborators None., Roberts JD., Tremblay-Gravel M., Giraldeau G., Cadrin-Tourigny J., L'Allier PL., Garceau P., Talajic M., Gagliano Taliun SA., Pinto YM., Rakowski H., Pantazis A., Bai W., Baksi J., Halliday BP., Prasad SK., Barton PJR., O'Regan DP., Cook SA., de Boer RA., Christiaans I., Michels M., Kramer CM., Ho CY., Neubauer S., HCMR Investigators None., Matthews PM., Wilde AAM., Tardif J-C., Olivotto I., Adler A., Goel A., Ware JS., Bezzina CR., Watkins H.
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.