A new polygenic risk score was significantly associated with hypertrophic cardiomyopathy diagnosis (HR 3.19; 95% CI 2.46-4.14 for the top 5% vs lower 95%).
Meta-Analysis (n=418,022)
Yes
Does a polygenic risk score predict the risk of hypertrophic cardiomyopathy development, imaging characteristics, and clinical outcomes?
A novel polygenic risk score for hypertrophic cardiomyopathy can predict disease development, associated imaging traits, and the risk of sudden cardiac death in sarcomere-negative patients.
Hazard Ratio: 3.19 (95% CI 2.46–4.14)
ABSTRACT Background Hypertrophic cardiomyopathy (HCM) is a heritable trait with marked variability in expression and outcomes. Our aims were to discover new genetic loci associated with HCM and to test the effect of a new polygenic risk score (PRS) on incidence, phenotype and outcomes, stratified by sarcomere genotype status. Methods A discovery genome-wide association study (GWAS) was performed on 2,284 HCM cases and 4,525 controls. Two fixed-effects meta-analyses combined our discovery GWAS with single-trait and multi-trait results from a published study. Discovered loci underwent comprehensive bioinformatic analysis including functional and druggability annotations. A PRS using loci from the two meta-analyses was evaluated for association with: HCM diagnosis in 411,213 individuals from UK Biobank (UKBB); imaging phenotypes in individuals without HCM; a composite endpoint (including all-cause mortality and transplantation) and sudden cardiac death (SCD) in 1,756 HCM cases. PRS analyses were stratified by sarcomere genotype status. Results Three loci were found in the discovery GWAS ( BAG3, FHOD3 and novel locus PPP1R3A ). In the meta-analyses, 70 unique loci were identified, four novel ( MYPN, YWHAE, NOS1AP and OBSCN ). Bioinformatic analyses identified NOS1AP as a candidate HCM gene. A new PRS was significantly associated with HCM diagnosis (hazard ratio HR 3.19, 95% CI:2.46–4.14, for top 5% vs lower 95%; HR 1.88, 95% CI:1.72–2.06, per SD increase). Significant associations were found between PRS and greater left ventricular (LV) wall thickness and higher LV ejection fraction in UKBB participants without HCM. Sarcomere-negative HCM cases in the top 20% of the PRS distribution had an increased risk of SCD (HR 2.72, 95% CI:1.03–7.17). Conclusions We report novel HCM loci. A new PRS predicted the risk of HCM development and associated imaging characteristics in the UKBB and outcomes in an HCM cohort.
Lopes et al. (2026) conducted a meta-analysis in Hypertrophic cardiomyopathy (n=418,022). Polygenic risk score (PRS) vs. Lower 95% of PRS distribution was evaluated on HCM diagnosis (HR 3.19, 95% CI 2.46-4.14). A new polygenic risk score was significantly associated with hypertrophic cardiomyopathy diagnosis (HR 3.19; 95% CI 2.46-4.14 for the top 5% vs lower 95%).