Polygenic susceptibility to dilated cardiomyopathy underlies peripartum, alcohol-induced, and cancer therapy-related cardiomyopathies
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".