Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect

Nat Genet. 2021 Feb;53(2):128-134. doi: 10.1038/s41588-020-00762-2. Epub 2021 Jan 25.

Abstract

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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Grant support