Highlights
Polygenic susceptibility for hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) exists on an overlapping but opposing spectrum, where risk for one phenotype can actively protect against the other.
In a cohort of nearly 50,000 participants, a 1-SD increase in HCM polygenic score (PGS) was associated with an 80% increased risk of HCM and a 31% decreased risk of DCM.
The inclusion of polygenic background significantly improves the predictive accuracy of clinical models beyond traditional factors like age, sex, and the presence of rare monogenic variants.
The Clinical Paradox of Cardiomyopathy Penetrance
Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) have traditionally been viewed as distinct clinical entities. HCM is characterized by unexplained left ventricular hypertrophy, often driven by hypercontractility and impaired relaxation, while DCM is defined by ventricular dilation and systolic dysfunction. Despite these opposing morphologies, both conditions are frequently caused by mutations in the same sarcomeric genes, such as MYH7 or TTN. A long-standing challenge in clinical genetics has been the phenomenon of variable expressivity and incomplete penetrance: why do two individuals with the same pathogenic variant develop vastly different clinical outcomes, or in some cases, no disease at all?
Emerging evidence suggests that the ‘monogenic’ label may be an oversimplification. Instead, the clinical manifestation of these diseases is likely a product of the interplay between rare, high-effect variants and a broad background of common, low-effect genetic variants. A recent study published in JAMA Cardiology by Abramowitz and colleagues provides critical insights into this polygenic-monogenic interaction, suggesting that our genetic background acts as a bidirectional modifier of cardiomyopathy risk.
Study Design and Methodology
This cross-sectional study utilized data from the Penn Medicine BioBank (PMBB), a massive repository containing electronic health records (EHR) and genomic data from volunteers enrolled between 1994 and 2022. The researchers analyzed 49,434 participants with a median age of 57 years, of whom 50.3% were male. The primary goal was to determine how normalized polygenic scores (PGSs) for HCM and DCM, alongside the carrier status of established rare pathogenic variants, influenced cardiac structure and disease prevalence.
The researchers defined HCM and DCM using a combination of ICD-9/10 diagnosis codes, procedure codes, and quantitative echocardiographic measurements, including left ventricular ejection fraction (LVEF), left ventricular internal diameter at end-diastole (LVIDd), and interventricular septal (IVS) thickness. By integrating these data points, the team could observe the subtle structural shifts associated with different genetic risk profiles before a formal diagnosis was even reached.
Results: Quantifying the Polygenic Influence
The study’s findings reinforce the idea that HCM and DCM are not just distinct diseases but are polar opposites on a physiological spectrum. The impact of polygenic scores on echocardiographic parameters was striking and highly significant.
The Impact of HCM Polygenic Risk
A 1-SD increase in the HCM PGS was associated with a 1.1% increase in LVEF (95% CI, 0.9 to 1.3), a 0.79-mm decrease in LVIDd (95% CI, -0.92 to -0.67), and a 0.18-mm increase in IVS thickness (95% CI, 0.14 to 0.22). Clinically, this translates to a heart that is thicker and more hypercontractile. Correspondingly, each standard deviation increase in the HCM PGS resulted in an 80% increase in the risk of being diagnosed with HCM (OR 1.8; 95% CI, 1.6-2.0).
The Impact of DCM Polygenic Risk
Conversely, a 1-SD increase in the DCM PGS was associated with a 2.0% decrease in LVEF (95% CI, -2.2 to -1.8) and a 1.0-mm increase in LVIDd (95% CI, 0.93 to 1.1). This profile describes a heart that is more dilated and has weaker pumping capacity. The risk of a DCM diagnosis increased by 60% per SD of the DCM PGS (OR 1.6; 95% CI, 1.5-1.7).
The Inverse Relationship: A Genetic Protection
Perhaps the most intriguing finding of the study is the bidirectional and protective nature of these polygenic backgrounds. The researchers discovered that a high polygenic risk for HCM actually served as a protective factor against DCM, and vice versa. Specifically, a 1-SD increase in the HCM PGS was associated with a 31% decreased risk of DCM (OR 0.69). Similarly, a 1-SD increase in the DCM PGS was associated with a 31% decreased risk of HCM (OR 0.69).
This suggests that the common variants that predispose an individual to a hypercontractile, thick-walled heart (HCM) may effectively buffer the deleterious effects of variants that would otherwise lead to a dilated, weak-walled heart (DCM). This ‘genetic tug-of-war’ helps explain why some carriers of pathogenic variants remain asymptomatic for decades; their polygenic background may be pulling their cardiac morphology in the opposite direction of their monogenic risk.
Clinical Implications: Improving Disease Prediction
From a clinical standpoint, the study demonstrates that monogenic and polygenic risk factors provide independent and additive information. When the researchers added PGS data to models that already included age, sex, and monogenic variant status, the discrimination of the models (measured by the area under the receiver operating characteristic curve, or AUC) improved significantly for both HCM (improvement of 0.043) and DCM (improvement of 0.045).
For clinicians, this means that genetic testing should eventually move toward a more integrated approach. Knowing that a patient carries a pathogenic mutation in MYH7 is important, but knowing their polygenic score could help determine if they are at high risk for early-onset, severe disease or if they are likely to remain in a subclinical state. This could refine screening intervals, influence family counseling, and potentially guide early therapeutic interventions.
Expert Commentary and Limitations
The findings align with the ‘sarcomere power’ model of cardiomyopathy, where mutations that increase the energy consumption and force of the sarcomere lead to HCM, while those that decrease force and stability lead to DCM. The polygenic background likely influences the baseline ‘set point’ of this sarcomeric tension. If a patient’s common variants lean toward high tension, they may develop HCM even without a major mutation, or they may exhibit extreme hypertrophy if a mutation is present.
However, the study has limitations. The Penn Medicine BioBank, while large, may not fully represent the global population, and the performance of polygenic scores can vary significantly across different ancestral backgrounds. Additionally, while the EHR-based diagnosis is efficient for large-scale studies, it may miss subtle or early-stage phenotypes that a dedicated prospective clinical trial would capture. Further research is needed to determine the cost-effectiveness of integrating polygenic scores into routine cardiogenetic workflows.
Conclusion
The research by Abramowitz et al. highlights that the risk of inherited cardiomyopathy is not a binary state dictated solely by a single gene. Instead, it is a nuanced balance between rare pathogenic variants and a broad polygenic background. By recognizing that HCM and DCM risk exist on an opposing spectrum, clinicians can better understand the variable penetrance seen in families and move closer to truly personalized cardiovascular medicine.
References
Abramowitz SA, Hoffman-Andrews L, Zhang D, et al. Polygenic Background and Penetrance of Pathogenic Variants in Hypertrophic and Dilated Cardiomyopathies. JAMA Cardiol. Published online December 23, 2024. doi:10.1001/jamacardio.2025.4739.