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

Item Type:Article
Title:Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity
Creators Name:Harper, A.R. and Goel, A. and Grace, C. and Thomson, K.L. and Petersen, S.E. and Xu, X. and Waring, A. and Ormondroyd, E. and Kramer, C.M. and Ho, C.Y. and Neubauer, S. and Tadros, R. and Ware, J.S. and Bezzina, C.R. and Farrall, M. and Watkins, H.
Abstract: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; h(2)(g) = 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.
Keywords:Blood Pressure, Cardiac Myosins, Carrier Proteins, Case-Control Studies, Formins, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Hypertrophic Cardiomyopathy, Myosin Heavy Chains, Risk Factors, Sarcomeres, Single Nucleotide Polymorphism
Source:Nature Genetics
ISSN:1061-4036
Publisher:Nature Publishing Group
Volume:53
Number:2
Page Range:135-142
Date:February 2021
Additional Information:Jeanette Schulz-Menger is a HCMR Investigator.
Official Publication:https://doi.org/10.1038/s41588-020-00764-0
PubMed:View item in PubMed

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