Zheng Sean L, Jurgens Sean J, McGurk Kathryn A, Xu Xiao, Grace Chris, Theotokis Pantazis I, Buchan Rachel J, Francis Catherine, de Marvao Antonio, Curran Lara, Bai Wenjia, Pua Chee Jian, Tang Hak Chiaw, Jorda Paloma, van Slegtenhorst Marjon A, Verhagen Judith M A, Harper Andrew R, Ormondroyd Elizabeth, Chin Calvin W L, Pantazis Antonis, Baksi John, Halliday Brian P, Matthews Paul, Pinto Yigal M, Walsh Roddy, Amin Ahmad S, Wilde Arthur A M, Cook Stuart A, Prasad Sanjay K, Barton Paul J R, O'Regan Declan P, Lumbers R T, Goel Anuj, Tadros Rafik, Michels Michelle, Watkins Hugh, Bezzina Connie R, Ware James S
National Heart Lung Institute, Imperial College London, London, UK.
Medical Research Council Laboratory of Medical Sciences, Imperial College London, London, UK.
Nat Genet. 2025 Mar;57(3):563-571. doi: 10.1038/s41588-025-02094-5. Epub 2025 Feb 18.
Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts. We show that higher PGS significantly increases the risk of HCM in the general population, particularly among pathogenic variant carriers, where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. Among relatives of HCM probands, PGS stratifies risks of developing HCM and adverse outcomes. Finally, among HCM cases, PGS strongly predicts the risk of adverse outcomes and death. These findings support the broad utility of PGS across clinical settings, enabling tailored screening and surveillance and stratification of risk of adverse outcomes.
肥厚型心肌病（HCM）是发病和死亡的重要原因，约三分之一的病例中发现了致病变异。大规模全基因组关联研究（GWAS）表明，常见的基因变异会增加患HCM的风险。在此，我们从HCM的GWAS和基因相关性状中得出多基因评分（PGS），并在英国生物银行、“十万基因组计划”和临床队列中测试其性能。我们发现，较高的PGS显著增加了普通人群患HCM的风险，尤其是在致病变异携带者中，最高和最低PGS五分位数人群的HCM外显率相差10倍。在HCM先证者的亲属中，PGS可对发生HCM和不良结局的风险进行分层。最后，在HCM病例中，PGS能强烈预测不良结局和死亡风险。这些发现支持了PGS在各种临床环境中的广泛应用，有助于进行针对性的筛查、监测以及对不良结局风险进行分层。
