Polygenic susceptibility to dilated cardiomyopathy underlies peripartum, alcohol-induced, and cancer therapy-related cardiomyopathies

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ABSTRACT Background Rare (monogenic) variants linked to non-ischemic dilated cardiomyopathy (DCM) are enriched among individuals with peripartum (PPCM), alcohol-induced (ALCM), and cancer therapy-related (CCM) cardiomyopathies, but are present in less than 15% of cases. Whether a common variant (polygenic) predisposition to DCM also pervades these secondary cardiomyopathies remains unclear. Methods We evaluated the association of a DCM polygenic score with PPCM, ALCM, and CCM in the Mass General Brigham (MGB) Biobank (n = 42,137), with replication in the UK Biobank (n = 295,160) and FinnGen (n = 417,950). We then assessed the proportion of cases with a monogenic variant and/or a high polygenic score (defined as > 80 th percentile of the score distribution). Finally, we queried medical charts to ascertain whether cardiomyopathy onset in those at high polygenic risk might have been heralded by relevant clinical risk factors. Results We identified 415 individuals with a secondary cardiomyopathy (30 with PPCM, 275 with ALCM, and 110 for CCM) across the three cohorts. The DCM polygenic score associated with PPCM (OR = 1.88 per 1 standard deviation (SD) increase in polygenic score, p= 0.001), ALCM (OR per SD = 1.38, p = 1.46E-07), and CCM (OR per SD = 1.58, p = 2.97E-06). Monogenic DCM variants were strongly associated with PPCM, ALCM, and CCM, but were present in less than 10% of cases. Roughly 40% of all secondary cardiomyopathy cases had a high polygenic score, which conferred ∼3-fold odds of cardiomyopathy (p <0.001). Most secondary cardiomyopathy cases lacked known antecedent clinical risk factors. Conclusion Cases of PPCM, ALCM, and CCM are enriched for monogenic DCM variants and a high DCM polygenic score, further supporting a shared genetic susceptibility influenced by distinct environmental precipitants. Considering both monogenic and polygenic risk for DCM may improve identification of individuals predisposed to secondary cardiomyopathies, particularly among those lacking established clinical risk factors.

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