Abstract Body (Do not enter title and authors here): Background: Hypertrophic cardiomyopathy (HCM) risk is incompletely explained by pathogenic variants and polygenic background. Mendelian randomization studies have implicated body mass index (BMI) as a modifiable risk factor for HCM in individuals with a pathogenic HCM variant (‘genotype-positive’; G+) and in those without (‘genotype-negative’; G-), and diastolic blood pressure (DBP) as a modifiable risk factor for genotype-negative HCM only.

Research Questions: How do BMI, DBP, and HCM polygenic risk influence HCM diagnoses and echocardiographic endophenotypes by genotype status?

Methods: Penn Medicine BioBank participants with and without HCM were identified using electronic health records. G+ participants carried pathogenic variants in definitive HCM genes. To avoid confounding, BMI and DBP were represented by polygenic scores (PGSs). PGSs for BMI, DBP, and common variant HCM risk were identified from the PGS Catalog (IDs PGS004150, PGS004604, PGS004910). Stratifying by pathogenic variant status (G+/G-), we tested PGS associations with HCM status with logistic regression. We evaluated their associations with interventricular septal thickness and left ventricular ejection fraction (EF) on echocardiogram using linear regression. Models included age and sex as covariates. Formal interaction testing between each PGS and monogenic variant status was performed.

Results: Among 32,615 unrelated participants, 363 (1.1%) were diagnosed with HCM. G+ status conferred a 58-fold increased HCM risk (p=2.6x10^-135). Estimated associations between BMI and HCM PGSs and HCM were positive regardless of pathogenic variant status (p<0.05 for HCM PGS only); DBP was associated with HCM only among G- individuals (OR 1.63; 95% CI 1.09 to 1.39; p=7.0x10^-4; Figure 1A). All PGSs were positively associated with septal thickness, a defining feature of HCM (Figure 1B). A significant (p<0.05) interaction term was observed between monogenic and polygenic HCM risk. DBP and BMI PGSs were negatively associated with EF among G- individuals, discordant with the typical HCM phenotype (Figure 1B).

Conclusions: Increased polygenic BMI, DBP, and HCM risk may promote septal thickening. The interaction between HCM PGS and variant carrier status suggests a synergistic role of common- and rare-variation directly related to HCM. In contrast, DBP appears to modify the risk of genotype-negative disease only. These findings suggest distinct roles of modifiable risk factors in G- and G+ HCM.