Pathogenic variants alone do not fully explain HCM risk. This analysis, presented at the American Heart Association (AHA) 2025 Scientific Sessions, evaluated how polygenic BMI, DBP, and HCM risk modify disease diagnosis and echocardiographic features in G+ and G- individuals.

The study included 32,615 unrelated participants from the Penn Medicine BioBank. Among them, 363 individuals (1.1%) were diagnosed with HCM. G+ participants carried pathogenic variants in definitive HCM genes. To reduce confounding, BMI and DBP were represented using polygenic scores derived from the Polygenic Score Catalog.

G+ status conferred a 58-fold increased risk of HCM (p=2.6×10⁻¹³⁵). Polygenic BMI and HCM risk scores were positively associated with HCM regardless of genotype status, although statistical significance was observed for the HCM polygenic score only. Polygenic DBP was associated with HCM risk exclusively in G- individuals (odds ratio 1.63; 95% confidence interval 1.09 to 1.39; p=7.0×10⁻⁴). All polygenic scores were positively associated with interventricular septal thickness. A significant interaction was observed between monogenic and polygenic HCM risk.

Polygenic BMI and DBP were negatively associated with left ventricular ejection fraction in G- individuals. These findings indicate that common and rare genetic variation interact to influence HCM expression, while DBP appears to modify risk primarily in genotype-negative disease.