Abstract 15276: Polygenic Susceptibility to Dilated Cardiomyopathy Underlies Peripartum, Alcoholic, and Chemotherapy-Induced Cardiomyopathies

Introduction: Rare (monogenic) variants linked to dilated cardiomyopathy (DCM) are enriched among individuals with peripartum (PPCM), alcoholic (ACM), and chemotherapy-induced cardiomyopathies (CCM), but are present in <15% of cases. Whether a common-variant (polygenic) susceptibility to DCM is also shared across these secondary cardiomyopathies is unknown. Methods: Cases of DCM, PPCM, ACM, and CCM were adjudicated using hospital billing codes only (in UK Biobank), or with additional chart reviews conducted by 2 medical doctors blinded to the genetic data (in Mass General Brigham [MGB] Biobank). A DCM polygenic score predicated on imaging-based measures of left ventricular structure and function was tested for association with each condition. In a subset of MGB Biobank participants with whole exome sequencing data, we determined the proportion of cases with a monogenic variant and/or a high (≥90 th percentile) polygenic score. Results: In MGB Biobank (n=30,837) and UK Biobank (n=304,687), 193 cases of PPCM (n=18), ACM (n=127) or CCM (n=48) were identified. A DCM polygenic score comprising 2.3 million common genetic variants associated comparably with DCM and all three secondary cardiomyopathies (meta-analyzed p<0.001 for all) ( Figure ). Among chart-validated phenotypes in MGB Biobank, cases had higher median polygenic score percentiles than controls (Controls=50; DCM=68; PPCM=86; ACM=70; CCM=59), and a high polygenic score conferred 3.3-fold odds of any secondary cardiomyopathy (p<0.001). In the whole exome sequencing subset (N=21,378; n=65 secondary cardiomyopathy cases), 9.2% of secondary cardiomyopathy cases harbored a monogenic variant, while 21.5% had a high polygenic score (including 1.5% who had both). Conclusion: Individuals with PPCM, ACM, and CCM are enriched for a high DCM polygenic score, further suggesting that these conditions arise from unique, extrinsic insults acting in the context of a common, underlying genetic susceptibility.