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

Common polygenic contribution to hypertrophic cardiomyopathy risk and imaging phenotypes, including in genotype-negative cases

A discovery genome-wide association study of 2,284 hypertrophic cardiomyopathy cases and 4,525 controls identified three loci: BAG3, FHOD3 and the novel locus PPP1R3A. Two meta-analyses combining these with a published study yielded 70 unique loci, four of them novel — MYPN, YWHAE, NOS1AP and OBSCN — with bioinformatic analyses nominating NOS1AP as a candidate gene. A polygenic risk score built from these loci was significantly associated with diagnosis in 411,213 UK Biobank participants (HR 3.19, 95% CI 2.46-4.14 for the top 5%; HR 1.88 per SD) and with greater left ventricular wall thickness in participants without the disease. Among 1,756 cases, genotype-negative patients in the top 20% of the score had an increased risk of sudden cardiac death (HR 2.72, 95% CI 1.03-7.17).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The most useful signal concerns genotype-negative cases: precisely the patients for whom genetics currently adds nothing in clinic, and where the polygenic score identifies excess sudden cardiac death risk. The confidence interval around the 2.72 hazard ratio nearly touches 1, so the estimate remains fragile and needs replication before entering any implantable defibrillator discussion. The score is also derived from largely European cohorts, which limits transportability.

Analysis by Dr Thibaut Benquey