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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by funding from the British Heart Foundation [RE/18/4/34215, FS/IPBSRF/22/27059, FS/15/81/31817, FS/ICRF/21/26019, RG/19/6/34387, RE/13/1/30181, BBC/F/21/220106]; the Medical Research Council [MC\_UP\_1605/13]; Wellcome Trust [107469/Z/15/Z]; the National Institute for Health Research (NIHR) Imperial College Biomedical Research Centre; NIHR Royal Brompton Cardiovascular Biomedical Research Unit; Sir Jules Thorn Charitable Trust [21JTA]; National Heart Lung Institute Foundation; Royston Centre for Cardiomyopathy Research; the Dutch Heart Foundation [03-007-2022-0035, CVON PRIME]; Rosetrees Trust; EJP-RD, Leducq Foundation [17CVD02]; Amsterdam Cardiovascular Sciences; European Commission [LSHM-CT- 2007-037273, HEALTH-F2-2013-601456]; European Joint Programme Rare Diseases [LQTS-NEXT, ZonMW project 40-46300-98-19009]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All patients gave written informed consent, and all studies were approved by the relevant regional research ethics committees, and adhered to the principles set out in the Declaration of Helsinki. The UK Biobank study was reviewed by the National Research Ethics Service (11/NW/0382, 21/NW/0157). The 100,000 Genomes Project was reviewed by the National Research Ethics Service (14/EE/1112 and 13/EE/032). The Royal Brompton Biobank was reviewed and approved by the South Central - Hampshire B Research Ethics Committee (09/H0504/104+5 and 19/SC/0257). The Erasmus Medical Center was reviewed and approved by the Erasmus MC Medical Ethical Review Committee. All Singaporean participants recruited from the National Heart Center Singapore gave written informed consent and the study was approved by the Singhealth Centralised Institutional Review Board (2020/2353) and the Singhealth Biobank Research Scientific Advisory Executive Committee (SBRSA 2019/001v1). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. PGS scores will be made available on the Polygenic Score Catalog ([www.pgscatalog.com][1]) upon publication following peer-review of the article. [1]: http://www.pgscatalog.com