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., Jurgens SJ., Thomson KL., Harper AR., Ormondroyd E., West DM., Xu X., Theotokis PI., Buchan RJ., McGurk KA., Mazzarotto F., Boschi B., Pelo E., Lee M., Noseda M., Varnava A., Vermeer AM., Walsh R., Amin AS., van Slegtenhorst MA., Roslin N., 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., Pinto YM., Rakowski H., Pantazis A., Baksi J., Halliday BP., Prasad SK., Barton PJ., O'Regan DP., Cook SA., de Boer RA., Christiaans I., Michels M., Kramer CM., Ho CY., Neubauer S., HCMR Investigators None., Matthews PM., Wilde AA., 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. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) as sociated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL , which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.