Utility of polygenic risk scores for dilated cardiomyopathy in the general population

Abstract Background Common genetic variation has been linked to an increased risk of developing dilated cardiomyopathy (DCM) in case-control studies. However, the phenotypic profile and biological mechanisms by which genetic background may predispose individuals to DCM and outcomes in the general population remain unclear. Aim The primary objectives of this study were twofold: (1) to validate a DCM polygenic score (PRS-1) based on a prior meta-analysis of case–control genetic association studies Tadros R et al. Nat Genet (2021); and (2) To apply this PRS, along with two recently developed PRSs for DCM PRS-2 from Zheng SL et al. Nat Genet (2024) and PRS-3 from Jurgens SJ et al. Nat Genet (2024) to a general population that underwent comprehensive longitudinal phenotypic assessments and had long-term outcomes available. Methods While the PRS-1 was derived from only 13 SNPs, PRS-2 and PRS-3 were generated from 709,534 and 1,072,247 SNPs, respectively with significant overlap between them. These DCM-PRSs were applied to an unselected community-based cohort (n=1897) aged 45 years, who underwent a physical examination, echocardiogram, and blood sample at baseline. Subsequent clinical outcomes were collected over a median 16 year follow-up (IQR: 15-17). Results No significant differences between the quartiles were present in terms of age, sex (48% male), and cardiovascular risk factors (CV-RF) (such as hypertension, diabetes, and coronary artery disease). However, linear regression models demonstrated a significant correlation between all DCM-PRSs and left ventricular (LV) parameters, including LV ejection fraction, LV end-systolic diameter, and LV end-diastolic diameter (Table). Multivariable regression analysis confirmed that these correlations were independent of age, sex, CV-RF, and population stratification (adjusted for the first 10 principal components PCs). During follow-up, 47 individuals developed DCM. A logistic regression analysis, using a 3:1 matched cohort of non-DCM vs. DCM individuals based on age and sex and adjusted for the same 10 PCs, found a significant correlation between DCM development and both PRS-1 OR=2.27 (1.06–4.85), p=0.03 and PRS-3 OR=2.63 (1.20–5.75), p=0.02, while PRS-2 did not show a significant association OR=1.85 (0.84–4.06), p=0.12. No association was found between the DCM-PRSs and heart failure (HF) biomarkers (aldosterone, natriuretic peptides, ST2, Galectin-3) or HF outcomes (all-cause mortality/HF hospitalization). Conclusion PRS-1 for DCM despite being derived from only 13 risk alleles, performs at least as well as the newer and more extensive PRSs, in its correlation with LV function, dimensions, and DCM development (except for PRS-2) in a general population. The absence of correlation between these DCM-PRSs and the renin-angiotensin-aldosterone system or natriuretic peptides suggests that genetic background influences LV traits through mechanisms independent of these biological pathways.