Key result
A polygenic risk score for dilated cardiomyopathy strongly predicted disease risk, with individuals in the top centile having a 7-fold increased risk compared to the bottom centile (OR 7.04).
Why the study?
Dilated cardiomyopathy is a leading cause of heart failure and cardiac transplantation, motivating research into its molecular etiology.
Meta-Analysis (n=1,213,412)
Yes
Odds Ratio: 7.04 (95% CI 2.42–20.52)
p-value: p=3.5 × 10−4
The identification of 80 genomic risk loci and 62 effector genes for dilated cardiomyopathy provides insights into its molecular etiology and suggests polygenic scores could inform future genetic testing strategies.
Should not yet alter DCM genetic testing; leaves open polygenic score utility pending prospective validation.
Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics.
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Zheng et al. (2024) conducted a meta-analysis in Dilated cardiomyopathy (n=1,213,412). Polygenic risk score (top centile) vs. Bottom centile of polygenic risk score was evaluated on Dilated cardiomyopathy risk (OR 7.04, 95% CI 2.42-20.52, p=3.5 × 10−4). A polygenic risk score for dilated cardiomyopathy strongly predicted disease risk, with individuals in the top centile having a 7-fold increased risk compared to the bottom centile (OR 7.04).
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