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Leveraging the shared and opposing genetic mechanisms in the heritable cardiomyopathies

Daria Kramarenko1,2,3, Poeya Haydarlou1, George Powell4

  • 1Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands.

Research Square
|February 6, 2026
PubMed

Insights

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) have opposing genetic links, yet share some genomic factors. This study identifies 100 loci, aiding in understanding heart muscle diseases and guiding precision medicine.

Area of Science:

  • Genetics
  • Cardiology
  • Genomic Medicine

Background:

  • Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are distinct heart muscle diseases with opposing phenotypes.
  • Both conditions can lead to severe heart failure and life-threatening arrhythmias.

Purpose of the Study:

  • To investigate the largely inverse genetic associations between DCM and HCM.
  • To identify genetic loci contributing to the cardiomyopathy spectrum and potential therapeutic targets.

Main Methods:

  • Genome-wide association study (GWAS) using data from 9,365 DCM cases, 5,900 HCM cases, and over 1.2 million controls.
  • Case-case GWAS approaches to model DCM and HCM as opposing genetic entities.
  • Development and validation of polygenic risk scores.

Main Results:

  • Identified 100 loci (17 novel) associated with the cardiomyopathy spectrum, with largely inverse associations between DCM and HCM.
  • Several identified loci, such as ADM and CACNA2D2, may represent therapeutic targets.
  • Polygenic risk scores demonstrated strong discrimination between DCM and HCM patients (AUC 0.78-0.84).

Conclusions:

  • The opposing genetic mechanisms of DCM and HCM suggest that therapies may have differential effects.
  • A shared genetic locus near CASQ2 and a concordant genomic component related to cardiometabolic health were identified.
  • This research defines the genomic architecture of major cardiomyopathy subtypes, paving the way for novel therapeutics and precision medicine in heart failure.

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