Evaluation of polygenic score for hypertrophic cardiomyopathy in the general population and across clinical settings

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with rare pathogenic variants found in about a third of cases (sarcomere-positive). Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes substantially to HCM risk. Here, we derive polygenic scores (PGS) from HCM GWAS, and multi-trait analysis of GWAS incorporating genetically-correlated traits, and test their performance in the UK Biobank, 100,000 Genomes Project, and across clinical cohorts. Higher PGS substantially increases population risk of HCM, particularly amongst sarcomere-positive carriers where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. In relatives of HCM patients, PGS stratifies risks of developing HCM and adverse outcomes. Finally, PGS strongly predicts risk of adverse outcomes in HCM, with a 4 to 6-fold increase in death between cases in the highest and lowest PGS quintiles. These findings promise broad clinical utility of PGS in the general population, in cases, and in families with HCM, enabling tailored screening and surveillance, and stratification of risk of adverse outcomes.