# Leveraging the shared and opposing genetic mechanisms in the heritable cardiomyopathies

## TL;DR

This study explores the genetic differences and similarities between two heart diseases, DCM and HCM, revealing shared and opposing genetic factors that could lead to better treatments.

## Contribution

The study identifies 100 genetic loci (17 novel) that distinguish DCM and HCM, revealing both opposing and shared genetic mechanisms.

## Key findings

- DCM and HCM show largely inverse genetic associations across multiple genomic levels.
- Polygenic risk scores derived from these loci strongly discriminate between DCM and HCM patients (AUC 0.78–0.84).
- A shared-effect analysis identifies a single locus near CASQ2 and a concordant genomic component linked to cardiometabolic health.

## Abstract

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are heart muscle diseases with largely opposing structural and functional phenotypes. Yet, both may lead to the same devastating outcomes of advanced heart failure and life-threatening arrhythmias. Using genome-wide association data from 9,365 DCM cases, 5,900 HCM cases, and over 1.2 million controls, we show that DCM and HCM are largely inversely associated across multiple genomic levels. Modeling both disorders as opposing genetic entities, in case-case GWAS approaches, we identify 100 loci (17 novel) underlying the cardiomyopathy spectrum. Several loci map to potential therapeutic targets (e.g., ADM, CACNA2D2), and polygenic risk scores derived from these data show strong discrimination between DCM and HCM patients in external datasets (AUC 0.78–0.84; AUPRC ~ 0.85). The pervasive opposing associations suggest that cardiomyocyte-directed therapies may often have opposite effects in DCM versus HCM. Nevertheless, a shared-effect analysis reveals a single locus — near the calcium-buffering gene CASQ2 — and also identifies a concordant genomic component associated with cardiometabolic health and extracardiac risk factors. By leveraging the shared and opposing genetic mechanisms of DCM and HCM, our work defines the genomic architecture of major cardiomyopathy subtypes and suggests new directions for therapeutics and precision medicine in heart failure.