Hypertrophic cardiomyopathy: a genome wide association meta-analysis and polygenic risk score.

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. Method(s): 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. Result(s): 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. Sarcomerenegative 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). Conclusion(s): 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. Copyright © 2026, Posted by openRxiv