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

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.