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Updated: Nov 20, 2025

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model

Published on: August 8, 2022

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

Andrew R Harper1,2, Anuj Goel1,2, Christopher Grace1,2

  • 1Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, Oxford, UK.

Nature Genetics
|January 26, 2021
PubMed

Insights

Genetic factors significantly influence hypertrophic cardiomyopathy (HCM), a serious heart condition. Common genetic variants and modifiable risk factors like blood pressure play key roles in HCM development and severity.

Area of Science:

  • Cardiovascular Genetics
  • Genomics
  • Heart Disease Research

Background:

  • Hypertrophic cardiomyopathy (HCM) is a common yet serious genetic heart disorder.
  • Existing research links rare sarcomere gene variants to HCM, but this doesn't explain the full picture of phenotypic heterogeneity or cases lacking these variants.

Purpose of the Study:

  • To investigate the genetic architecture of HCM beyond rare sarcomere variants.
  • To identify common genetic variants and modifiable risk factors contributing to HCM.
  • To explore the clinical actionability of genetic insights and risk factors in HCM.

Main Methods:

  • Conducted a genome-wide association study (GWAS) involving 2,780 HCM cases and 47,486 controls.
  • Calculated single-nucleotide polymorphism (SNP) heritability to assess polygenic influence, particularly in sarcomere-negative HCM.
  • Developed and validated a genetic risk score (GRS) for HCM and used Mendelian randomization to identify modifiable risk factors.

Main Results:

  • Identified 12 novel genome-wide-significant loci associated with HCM susceptibility.
  • Demonstrated a strong polygenic influence on HCM, especially in sarcomere-negative cases (h²g = 0.34 ± 0.02).
  • A GRS significantly impacted HCM odds and phenotypic severity; Mendelian randomization linked diastolic blood pressure (DBP) to a fourfold increased HCM risk in sarcomere-negative cases.

Conclusions:

  • Common genetic variants play a substantial role in HCM pathogenesis, contributing to phenotypic heterogeneity.
  • Modifiable risk factors, notably diastolic blood pressure, are crucial for sarcomere-negative HCM and present actionable targets.
  • These findings suggest a paradigm shift towards integrating polygenic risk and modifiable factors for clinical management of HCM.

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