Background: Dilated Cardiomyopathy (DCM) is characterised by left ventricular dilation associated with systolic dysfunction and is a common cause of heart failure. Currently, pathogenic variants are identified in 20-40% of patients with familial DCM while most patients have an unknown cause. Here, we aimed to assess polygenic contribution to familial DCM and to assess polygenic inheritance of common DCM co-morbidities.
Methods: Polygenic risk scores (PRS) for indexed left ventricular end-systolic volume, (DCM-PRS), were calculated in two cohorts of familial DCM patients (Cohort_1: probands, n=76; affected relatives, n=176; unaffected relatives, n=153 and Cohort_2 = 108 probands). PRS results were distributed against a healthy control population (n=1,127). P/LP variants in DCM-associated genes were present in 48% probands. Odds ratios (OR) for disease outcomes were identified using logistic mixed effects models, including as a random effect a genetic relatedness matrix calculated by PLINK, followed by Wald tests.
Results: DCM-PRS in DCM probands was significantly higher than the healthy controls (64th percentile median; P<0.001). Further, in both Cohorts, the median DCM-PRS in probands with pathogenic/likely pathogenic variants was significantly higher than controls (63rd percentile median; P=0.032) and in probands without pathogenic/likely pathogenic variants (64th percentile median; P=0.001). In DCM families, the odds of being an affected family member increased 1.48-fold per unit of PRS standard deviation (SD) when compared to controls (P<0.001) and 1.30-fold per SD when compared with unaffected family members (P=0.063).
Conclusion: The results presented here suggest that the collective effects of common variants may be a key determinant of DCM in a subset of families, particularly in those in whom a causative rare variant has not been identified.