Introduction
Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with cardiovascular diseases. In this setting, polygenic risk scores (PRS) have emerged as promising tools for modifying and refining individual risk estimates [1]. Substantial technological and methodological advances since the Human Genome Project have enabled large-scale, population-based genetic profiling.
In contrast to polygenic risk, monogenic disease–causing variants are typically rare (minor allele frequency <1%) and confer large effect sizes; however, such variants are detected in only a small proportion of affected individuals and account for a limited fraction of the heritable risk observed in familial aggregation studies of cardiovascular disease [2,3)]. Over the past 15 years, progressively larger GWAS have consistently demonstrated that most cardiovascular diseases have a predominantly polygenic genetic architecture.
What are PRS?
PRSs, also referred to as genomic risk scores, represent the weighted sum of the risk conferred by multiple disease-associated single nucleotide variants (SNVs) across the genome. Constructing a PRS requires a list of SNVs along with their corresponding effect sizes—quantitative measures of each variant’s association with the disease—typically derived from an external dataset such as a GWAS.
Rather than focusing on a single causal variant, PRS evaluate the cumulative contribution of many variants, each exerting a small effect on disease risk, to generate a composite score that reflects overall genetic susceptibility. In essence, PRS leverage subsets of individual genotypes to capture the heritable component of common traits, thereby enabling the stratification of disease risk within a population.
PRS in Cardiomyopathies
From monogenic to polygenic cardiomyopathies
Historically, hypertrophic (HCM) and dilated cardiomyopathies (DCM) have been characterized as Mendelian disorders caused by rare, high-impact variants. However, growing evidence highlights a substantial polygenic contribution to disease risk, supporting the emerging concept of a “monogenic–polygenic continuum” in which both rare and common genetic variants interact to shape individual susceptibility and clinical presentation [4,5].
Polygenic risk scores for HCM
Large-scale GWAS demonstrate that common genetic variation makes a significant contribution to the risk of HCM [6,7] . In individuals who lack pathogenic variants in sarcomeric genes, overall disease susceptibility is likely driven by the distribution of polygenic risk in combination with causal clinical and environmental risk factors. In sarcomere-positive families, currents PRS are associated with disease penetrance, age at onset, and clinical outcomes among carriers of pathogenic variants. Among HCM cases, higher PRS strongly predict adverse outcomes, including mortality. In sarcomere-negative patients with HCM and their relatives, clinical management may be substantially improved by recognizing the strong influence of polygenic risk as a major modifiable risk factor. However, the clinical utility of PRS requires further evaluation in adequately powered longitudinal studies of HCM disease progression.
Polygenic risk scores for DCM
Recent GWAS and PRS analyses have substantially advanced our understanding of the contribution of common genetic variants to DCM [8]. Meta-analyses have identified multiple DCM-associated genes [9,10], including those linked to MRI-derived left ventricular (LV) traits [11)]. PRS have the potential to inform personalized therapy by identifying patients more likely to experience myocardial recovery and improved cardiac function in response to pharmacological interventions. Additionally, PRS have the potential to guide arrhythmic risk prediction and could eventually be integrated into clinical decision-making for prophylactic implantable cardioverter-defibrillator (ICD) implantation. However, at present, PRS are not yet validated for this purpose, and it remains uncertain whether they can meaningfully improve existing risk stratification strategies for the primary prevention of sudden cardiac death (SCD).
Polygenic background and variant penetrance across HCM and DCM Across HCM and DCM cardiomyopathies, polygenic background shapes both the likelihood that rare pathogenic variants manifest as clinical disease and the direction of ventricular remodelling. In the Penn Medicine BioBank [12], disease‑specific polygenic scores showed clear and opposing associations across phenotypes, reflecting an overlapping but antagonistic polygenic spectrum.
A higher HCM polygenic score was associated with a more forcefully contracting, concentrically remodelled heart: slightly higher ejection fraction, smaller left ventricular size, and thicker septal walls. Each one–standard deviation increase in the HCM score was linked to an 80% higher risk of HCM and a 31% lower risk of DCM. In contrast, a higher DCM polygenic score showed the reverse pattern. It was associated with lower ejection fraction, larger left ventricular size, a 60% higher risk of DCM, and a 31% lower risk of HCM.
Among carriers of pathogenic variants in established cardiomyopathy genes, rare variant status and PRS were independently associated with disease and quantitative traits. Incorporation of PRS improved discrimination beyond clinical covariates alone, indicating that common variants substantially modulate disease penetrance and ventricular phenotype in genetically predisposed individuals [13].
Clinical translation and future directions in inherited cardiomyopathy clinics
Clinical translation and future directions in inherited cardiomyopathy clinics: potential clinical use cases (risk stratification of relatives, tailoring surveillance intensity, interpretation of genotype‑negative or phenocopy cases), current limitations (ancestry transferability, calibration, ethical and communication considerations), and research priorities for integrating PRS into ESC cardiomyopathy pathways [14,15].
Conclusions
A major public health priority is the identification of individuals at high risk for specific diseases to enable targeted screening and preventive interventions. Although polygenic risk scores are already commercially available and, in some settings, are being used by clinicians and patients despite limited guidance on their appropriate application and target populations, as highlighted by a recent systematic review, their clinical utility in the management of cardiomyopathies has not yet been established [16].
Emerging evidence nevertheless indicates that PRS provide biologically meaningful information beyond rare variant status and clinical covariates, with the potential to refine risk stratification, penetrance assessment, and phenotypic interpretation in inherited cardiomyopathy. Until robust validation, calibration, and equitable implementation frameworks are in place, access to expert genetic counselling remains essential to support appropriate interpretation and communication of PRS-derived risk.
Meanwhile, other areas of cardiovascular research continue to expand in this context. In recent years, PRS have gained increasing attention as a promising approach for more personalized cardiovascular risk prediction [17], particularly because the traditional SCORE2 cardiovascular risk assessment tool may underestimate risk in certain populations. Moreover, the growing catalog of common genetic variants associated with atrial fibrillation (AF) has enabled the development of AF-specific PRS, which have demonstrated progressively improved predictive accuracy [3,18,19].