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The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

Original publication

DOI

10.1038/s41588-020-00762-2

Type

Journal article

Journal

Nature genetics

Publication Date

02/2021

Volume

53

Pages

128 - 134

Addresses

Cardiovascular Genetics Center, Montreal Heart Institute, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada. rafik.tadros@umontreal.ca.

Keywords

Heart Ventricles, Humans, Cardiomyopathy, Dilated, Cardiomyopathy, Hypertrophic, Genetic Predisposition to Disease, Case-Control Studies, Ventricular Function, Left, Gene Frequency, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study, Kaplan-Meier Estimate