Abstract 4139238: A Multi-Population-First Approach Leveraging UK Biobank (UKBB) and All of Us (AoU) Datasets Reveals Higher Cardiomyopathy Variant Burden in Individuals with Myocarditis

Intro: Myocarditis is an inflammatory cardiac condition that may progress to dilated (DCM) or arrhythmic (ACM) cardiomyopathy. Prior cohort studies indicate genetic factors significantly influence myocarditis susceptibility and outcomes; yet, this has not been studied at a population level, which holds potential for clinical risk prediction. Objective: To investigate DCM and ACM gene variant burden and clinical consequences by a multi-population approach encompassing diverse genetic ancestries. Methods: Individuals with exome sequencing (ES) in UKBB and AoU were included, and poor-quality samples excluded. Individuals with myocarditis were identified by ICD code and compared with myocarditis-neg population. Cardiomyopathy (CM) genes in ClinGen DCM- and ARVC-associated genes with at least moderate evidence of disease causality were included and filtered by our previously published variant pipeline and ClinVar 2* criteria for pathogenic/likely pathogenic (P/LP). Cardiac phenotype and CM variant burden were analyzed by chi-squared analysis. Results: 200,580 individuals in UKBB and 230,013 in AoU had ES. 137 in UKBB and 284 in AoU had myocarditis. Myocarditis cohorts in both populations had increased phenotypic burden of CM, ventricular arrhythmia, and HF vs myocarditis-neg. Myocarditis-pos showed increased CM (16.8% vs 0.2%); VA (10.9% vs 0.9%) and HF (32.8% vs 3.1%) in UKBB (p<0.001). Similarly in AoU, 44.5% of myocarditis-pos had CM (vs 2.8%); 22.3% had VA (vs 1.6%), and 55.8% had HF (vs 5.8%) when compared to myocarditis-neg. UKBB had increased DCM and ACM variant burden in myocarditis-pos cohort: 9.5% (5) with DCM ClinVar 2* P/LP and 3.6% (5) with ACM ClinVar 2* P/LP compared to 0.3% (561) and 0.3% (578) in myocarditis-neg (p<0.001). Increased burden of DCM P/LPs by our peer-reviewed pipeline was noted in AoU myocarditis-pos (9.8%, 28) compared to AoU myocarditis-neg (6.2%, p=0.02). ACM variants were not significantly overrepresented in myocarditis cohort in AoU (p=0.4) but was underpowered to note significance by ClinVar2* P/LP. Conclusions: This study highlights a substantial burden of DCM and ACM variants in individuals with myocarditis, particularly in UKBB. The differential significance in AoU may represent diverse genetic ancestries and differences in recruitment methods. Future analyses include determining variant burden by outcome and genetic-ancestry based variant analysis to elucidate genetic risk myocarditis susceptibility and disease progression.