Polygenic background bidirectionally modifies the penetrance of pathogenic variants in hypertrophic (HCM) and dilated (DCM) cardiomyopathies, diseases which exist with opposing morphological characteristics and genetic pathways, according to a large cross-sectional study conducted using data from the Penn Medicine BioBank (PMBB).
Hypertrophic vs Dilated Cardiomyopathy
HCMs and DCMs are the two most common types of cardiomyopathy. Both affect the heart’s ability to pump blood effectively but do so through different functional defects. HCM involves the thickening of the heart muscle, leading to impaired filling. DCM involves enlarged, weakened chambers leading to impaired pumping.
To investigate whether polygenic background modifies the pathogenicity of established rare variants associated with HCM and DCM, this cross-sectional study assessed 49 434 participants enrolled in PMBB between November 1994 and July 2022, with analysis conducted in June 2025. Normalised polygenic scores for HCM and DCM were then associated with relevant clinical and echocardiographic measures.
Opposite Effects of HCM and DCM Polygenic Score
An increased polygenic score for HCM was associated with a 1.1% increase in left ventricular ejection fraction, a 0.79 mm decrease in left ventricular internal diameter, and a 0.18 mm increase in interventricular septal thickness. Additionally, a one standard deviation increase in polygenic score for HCM was also associated with an 80% increased risk of HCM, and a 31% decreased risk of DCM.
Conversely, a one standard deviation increase in polygenic score for DCM had opposing effects: 2.0% decreased left ventricular ejection fraction, 1.0 mm increased left ventricular internal diameter, 60% increased risk of DCM, and 31% decreased risk of HCM. DCM polygenic score was not significantly associated with interventricular septal thickness.
Implications For Cardiomyopathy Treatment
These results suggest that a patient’s risk of HCM and DCM are modified by polygenic background. This finding may provide clinical value by helping to understand the underlying pathways at play in these inherited cardiomyopathies, leading to developments of new preventative strategies and treatments. Being able to analyse a patient’s polygenic background may also allow more accurate clinical predictions of these conditions and allow measures to be taken earlier in the timeline of disease progression.
However, it remains to be seen whether polygenic susceptibility for one disease protects against monogenic risk for the other. Future studies will be required to elucidate the possible link here.
Reference
Abramowitz SA et al. Polygenic background and penetrance of pathogenic variants in hypertrophic and dilated cardiomyopathies. JAMA Cardiol. 2025; DOI: 10.1001/jamacardio.2025.4739
