Abstract 15670: Clinical Relevance of a Polygenic Susceptibility to Dilated Cardiomyopathy

Introduction: Both rare and common genetic variants have been associated with dilated cardiomyopathy (DCM), but their contributions to DCM risk in the context of clinical factors remains unexplored. Methods: In the UK Biobank, we identified carriers of rare, monogenic variants of relevance to DCM (ClinGenLOF), and also computed a genome-wide, common-variant (polygenic) score (GPS) based on imaging-derived measures of left ventricular structure and function. We evaluated the contributions of ClinGenLOF status, the GPS, and clinical factors to incident DCM through measures of relative risk, phenotypic variance explained (i.e. population attributable fraction, PAF), and discrimination. Results: In 160,485 UK Biobank participants, mean age was 56.5 (SD 8.1), 89,888 (56%) were female, and 226 developed DCM during a median of 10.9 years of follow-up. ClinGenLOF carriers had the highest hazards of disease (HR=14.5, 95%CI: 9.43 to 22.11), followed by atrial fibrillation (HR=3.25, 95%CI:1.94 to 5.48), and chronic kidney disease (2.56 95%CI:0.81 to 8.12). In contrast, hypertension accounted for the greatest proportion of DCM risk in the population (PAF=23.2%) followed by having a high (>80th percentile) polygenic score (PAF= 17.9%). On top of a reference model, improvements in discrimination were individually greatest with addition of ClinGenLOF status (delta C-index = 0.049) or the GPS (delta C-index = 0.031), comparable to the addition of all clinical factors combined (delta C-index = 0.032; Figure ). When added sequentially to a model inclusive of clinical factors, ClinGenLOF status (delta C-index = 0.046) and GPS (additional delta C-index = 0.021) further improved discrimination. Conclusions: Rare, monogenic variants, a polygenic score, and clinical factors all contribute substantially to risk of DCM. Considering cumulative genetic (monogenic and polygenic) risk on top of clinical factors improves the prediction of incident DCM in the general population.