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Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity

2021; Nature Portfolio; Volume: 53; Issue: 2 Linguagem: Inglês

10.1038/s41588-020-00764-0

1546-1718

Andrew R. Harper, Anuj Goel, Christopher Grace, Kate Thomson, Steffen E. Petersen, Xiao Hua Xu, Adam Waring, Elizabeth Ormondroyd, Christopher M. Kramer, Carolyn Y. Ho, Stefan Neubauer, Paul Kolm, Raymond Y. Kwong, Sarahfaye Dolman, Patrice Desvigne‐Nickens, John Dimarco, Nancy L. Geller, Dong‐Yun Kim, Cheng Zhang, William S. Weintraub, Theodore P. Abraham, Lisa Anderson, Evan Appelbaum, Camillo Autore, Colin Berry, Elena Biagini, William Bradlow, Chiara Bucciarelli‐Ducci, Amedeo Chiribiri, Lubna Choudhury, Andrew M. Crean, Dana Dawson, Milind Y. Desai, Eleanor Elstein, Andrew Flett, Matthias G. Friedrich, Stephen B. Heitner, Adam Helms, Daniel Jacoby, Han Kim, Bette Kim, Éric Larose, Masliza Mahmod, Heiko Mahrholdt, Martin S. Maron, Gerry P McCann, Michelle Michels, Saidi Mohiddin, Sherif F. Nagueh, David E. Newby, Iacopo Olivotto, Anjali Owens, François Pierre-Mongeon, Sanjay Prasad, Ornella Rimoldi, Michael Salerno, Jeanette Schulz‐Menger, Mark V. Sherrid, Peter Swoboda, Albert C. van Rossum, Jonathan W. Weinsaft, James A. White, Eric E. Williamson, Rafik Tadros, James S. Ware, Connie R. Bezzina, Martin Farrall, Hugh Watkins,

Congenital heart defects research

Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic heterogeneity. Moreover, most patients do not carry such variants. We report a genome-wide association study of 2,780 cases and 47,486 controls that identified 12 genome-wide-significant susceptibility loci for HCM. Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM (64% of cases; h2g = 0.34 ± 0.02). A genetic risk score showed substantial influence on the odds of HCM in a validation study, halving the odds in the lowest quintile and doubling them in the highest quintile, and also influenced phenotypic severity in sarcomere variant carriers. Mendelian randomization identified diastolic blood pressure (DBP) as a key modifiable risk factor for sarcomere-negative HCM, with a one standard deviation increase in DBP increasing the HCM risk fourfold. Common variants and modifiable risk factors have important roles in HCM that we suggest will be clinically actionable. Genome-wide association analyses identify 12 susceptibility loci for hypertrophic cardiomyopathy (HCM). A genetic risk score for HCM was associated with disease status in a validation study and influenced phenotypic severity in carriers of risk variants in sarcomere genes.