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

Sean L. Zheng; Sean J. Jurgens; Kathryn A. McGurk; Xiao Xu; Chris Grace; Pantazis I. Theotokis; Rachel J. Buchan; Catherine Francis; Antonio de Marvao; Lara Curran; Wenjia Bai; Chee Jian Pua; Hak Chiaw Tang; Paloma Jorda; Marjon A. van Slegtenhorst; Judith M. A. Verhagen; Andrew R. Harper; Elizabeth Ormondroyd; Calvin W. L. Chin; James S. Ware; Antonio de Marvao; Antonis Pantazis; John Baksi; Brian P. Halliday; Paul Matthews; Yigal M. Pinto; Roddy Walsh; Ahmad S. Amin; Arthur A. M. Wilde; Stuart A. Cook; Sanjay K. Prasad; Paul J. R. Barton; Declan P. O’Regan; R. T. Lumbers; Anuj Goel; Rafik Tadros; Michelle Michels; Hugh Watkins; Connie R. Bezzina; HCM GWAS Collaborators

doi:10.1038/s41588-025-02094-5

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

Sean L. Zheng, Sean J. Jurgens, Kathryn A. McGurk, Xiao Xu, Chris Grace, Pantazis I. Theotokis, Rachel J. Buchan, Catherine Francis, Antonio de Marvao, Lara Curran, Wenjia Bai, Chee Jian Pua, Hak Chiaw Tang, Paloma Jorda, Marjon A. van Slegtenhorst, Judith M. A. Verhagen, Andrew R. Harper, Elizabeth Ormondroyd, Calvin W. L. Chin, James S. Ware^*Antonio de Marvao, Antonis Pantazis, John Baksi, Brian P. Halliday, Paul Matthews, Yigal M. Pinto, Roddy Walsh, Ahmad S. Amin, Arthur A. M. Wilde, Stuart A. Cook, Sanjay K. Prasad, Paul J. R. Barton, Declan P. O’Regan, R. T. Lumbers, Anuj Goel, Rafik Tadros, Michelle Michels, Hugh Watkins, Connie R. Bezzina, HCM GWAS Collaborators

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

3 Citations (Scopus)

Abstract

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.

Original language	English
Article number	3328
Pages (from-to)	563-571
Number of pages	9
Journal	Nat. Genet.
Volume	57
Issue number	3
Early online date	2025
DOIs	https://doi.org/10.1038/s41588-025-02094-5
Publication status	Published - Mar 2025

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Zheng, S. L., Jurgens, S. J., McGurk, K. A., Xu, X., Grace, C., Theotokis, P. I., Buchan, R. J., Francis, C., de Marvao, A., Curran, L., Bai, W., Pua, C. J., Tang, H. C., Jorda, P., van Slegtenhorst, M. A., Verhagen, J. M. A., Harper, A. R., Ormondroyd, E., Chin, C. W. L., ... HCM GWAS Collaborators (2025). Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings. Nat. Genet., 57(3), 563-571. Article 3328. https://doi.org/10.1038/s41588-025-02094-5

@article{3676e751585844ad8deea6c0131dddd3,

title = "Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings",

abstract = "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.",

author = "Zheng, {Sean L.} and Jurgens, {Sean J.} and McGurk, {Kathryn A.} and Xiao Xu and Chris Grace and Theotokis, {Pantazis I.} and Buchan, {Rachel J.} and Catherine Francis and {de Marvao}, Antonio and Lara Curran and Wenjia Bai and Pua, {Chee Jian} and Tang, {Hak Chiaw} and Paloma Jorda and {van Slegtenhorst}, {Marjon A.} and Verhagen, {Judith M. A.} and Harper, {Andrew R.} and Elizabeth Ormondroyd and Chin, {Calvin W. L.} and Ware, {James S.} and {de Marvao}, Antonio and Antonis Pantazis and John Baksi and Halliday, {Brian P.} and Paul Matthews and Pinto, {Yigal M.} and Roddy Walsh and Amin, {Ahmad S.} and Wilde, {Arthur A. M.} and Cook, {Stuart A.} and Prasad, {Sanjay K.} and Barton, {Paul J. R.} and O{\textquoteright}Regan, {Declan P.} and Lumbers, {R. T.} and Anuj Goel and Rafik Tadros and Michelle Michels and Hugh Watkins and Bezzina, {Connie R.} and {HCM GWAS Collaborators} and Ware, {James S.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = mar,

doi = "10.1038/s41588-025-02094-5",

language = "English",

volume = "57",

pages = "563--571",

journal = "Nat. Genet.",

issn = "1061-4036",

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Zheng, SL, Jurgens, SJ, McGurk, KA, Xu, X, Grace, C, Theotokis, PI, Buchan, RJ, Francis, C, de Marvao, A, Curran, L, Bai, W, Pua, CJ, Tang, HC, Jorda, P, van Slegtenhorst, MA, Verhagen, JMA, Harper, AR, Ormondroyd, E, Chin, CWL, Ware, JS, de Marvao, A, Pantazis, A, Baksi, J, Halliday, BP, Matthews, P, Pinto, YM , Walsh, R , Amin, AS , Wilde, AAM, Cook, SA, Prasad, SK, Barton, PJR, O’Regan, DP, Lumbers, RT, Goel, A, Tadros, R, Michels, M, Watkins, H, Bezzina, CR & HCM GWAS Collaborators 2025, 'Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings', Nat. Genet., vol. 57, no. 3, 3328, pp. 563-571. https://doi.org/10.1038/s41588-025-02094-5

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T1 - Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings

AU - Zheng, Sean L.

AU - Jurgens, Sean J.

AU - McGurk, Kathryn A.

AU - Xu, Xiao

AU - Grace, Chris

AU - Theotokis, Pantazis I.

AU - Buchan, Rachel J.

AU - Francis, Catherine

AU - de Marvao, Antonio

AU - Curran, Lara

AU - Bai, Wenjia

AU - Pua, Chee Jian

AU - Tang, Hak Chiaw

AU - Jorda, Paloma

AU - van Slegtenhorst, Marjon A.

AU - Verhagen, Judith M. A.

AU - Harper, Andrew R.

AU - Ormondroyd, Elizabeth

AU - Chin, Calvin W. L.

AU - Ware, James S.

AU - de Marvao, Antonio

AU - Pantazis, Antonis

AU - Baksi, John

AU - Halliday, Brian P.

AU - Matthews, Paul

AU - Pinto, Yigal M.

AU - Walsh, Roddy

AU - Amin, Ahmad S.

AU - Wilde, Arthur A. M.

AU - Cook, Stuart A.

AU - Prasad, Sanjay K.

AU - Barton, Paul J. R.

AU - O’Regan, Declan P.

AU - Lumbers, R. T.

AU - Goel, Anuj

AU - Tadros, Rafik

AU - Michels, Michelle

AU - Watkins, Hugh

AU - Bezzina, Connie R.

AU - HCM GWAS Collaborators

AU - Ware, James S.

PY - 2025/3

Y1 - 2025/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85218261775&partnerID=8YFLogxK

U2 - 10.1038/s41588-025-02094-5

DO - 10.1038/s41588-025-02094-5

M3 - Article

C2 - 39966645

SN - 1061-4036

VL - 57

SP - 563

EP - 571

JO - Nat. Genet.

JF - Nat. Genet.

IS - 3

M1 - 3328

ER -

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

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