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Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience
Sean J Jurgens1,2,3, Joel T Rämö2,3,4, Daria R Kramarenko1,5
1Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands.
Insights
This study identifies 70 genetic loci linked to dilated cardiomyopathy (DCM), a heart muscle disease. Findings reveal key roles for heart cells and muscle function, offering insights into DCM causes and potential treatments.
Area of Science:
- Cardiovascular Genetics
- Genomics
- Heart Disease Research
Background:
- Dilated cardiomyopathy (DCM) is a significant cause of heart failure, morbidity, and mortality.
- The underlying genetic mechanisms and causal pathways of DCM remain largely unknown.
- Understanding DCM's genetic architecture is crucial for developing effective treatments.
Purpose of the Study:
- To conduct a large-scale genome-wide association study (GWAS) for DCM.
- To identify novel genetic loci associated with DCM risk.
- To explore the biological pathways and potential causal factors implicated in DCM.
Main Methods:
- Performed a large-scale GWAS and multitrait analysis using 9,365 DCM cases and 946,368 controls.
- Utilized replication analyses in independent samples to validate findings.
- Conducted tissue, cell type, and pathway enrichment analyses.
- Constructed polygenic risk scores and performed Mendelian randomization analyses.
Main Results:
- Identified 70 genome-wide significant loci associated with DCM, with 63 prioritized genes.
- Enrichment analyses highlighted the importance of cardiomyocytes and the contractile apparatus in DCM.
- Polygenic risk scores predicted DCM across ancestries and associated with systolic heart failure.
- Mendelian randomization suggested higher body weight and systolic blood pressure as potential causes of DCM.
Conclusions:
- This study significantly advances the understanding of DCM's genetic basis.
- Findings implicate cardiomyocyte function and contractile processes in DCM pathogenesis.
- Identified actionable targets, such as body weight and blood pressure, for potential DCM intervention.
Abstract:
Dilated cardiomyopathy (DCM) is a heart muscle disease that represents an important cause of morbidity and mortality, yet causal mechanisms remain largely elusive. Here, we perform a large-scale genome-wide association study and multitrait analysis for DCM using 9,365 cases and 946,368 controls. We identify 70 genome-wide significant loci, which show broad replication in independent samples and map to 63 prioritized genes. Tissue, cell type and pathway enrichment analyses highlight the central role of the cardiomyocyte and contractile apparatus in DCM pathogenesis. Polygenic risk scores constructed from our genome-wide association study predict DCM across different ancestry groups, show differing contributions to DCM depending on rare pathogenic variant status and associate with systolic heart failure across various clinical settings. Mendelian randomization analyses reveal actionable potential causes of DCM, including higher bodyweight and higher systolic blood pressure. Our findings provide insights into the genetic architecture and mechanisms underlying DCM and myocardial function more broadly.
