Multi-omics Mendelian randomization analysis prioritizes DNA methylation-related mitochondrial genes in congenital heart disease

Résumé fourni par la source

Mitochondrial dysfunction has been increasingly recognized as a key pathophysiological contributor to congenital heart disease (CHD), yet its underlying genetic causal effects remain incompletely characterized. This study aimed to investigate the genetically supported associations between mitochondrial-related genes and CHD under a multi-omics framework. We integrated three-layer quantitative trait loci (QTL) data, including DNA methylation, gene expression and protein abundance, of 1,123 nuclear-encoded mitochondrial genes with genome-wide association study (GWAS) summary statistics of overall CHD from FinnGen R12. Summary-based Mendelian randomization (SMR) was applied to systematically evaluate associations between mitochondrial-related molecular traits and CHD. Heterogeneity in dependent instruments (HEIDI) test, colocalization analysis and single-nucleus transcriptomic analysis (GSE203274) were further performed to improve the reliability of identified candidate genes. After integrating three-layer multi-omics data, we identified 13 candidate genes associated with CHD susceptibility with evidence across at least two layers. These genes were predominantly involved in mitochondrial DNA (mtDNA) replication, mitochondrial translation, and mitochondrial respiratory chain, indicating that these pathways may mediate the pathogenic association between mitochondrial dysfunction and CHD. Among these promising genes, POLG and EARS2 were classified as Tier 1 candidates, with consistent directional associations observed in both peripheral blood and cardiac-specific datasets. POLG encodes the sole DNA polymerase responsible for mtDNA replication and repair, while EARS2 functions as a mitochondrial glutamate-tRNA synthetase to mediate the translation of respiratory chain complex subunits. Specifically, hypermethylation at cg04001880 and cg22187094 was associated with higher POLG expression and increased CHD susceptibility, whereas hypermethylation at cg03187795 was linked to lower EARS2 expression and reduced CHD-related risk. Independent single-nucleus transcriptomic data (GSE203274) provided suggestive supporting evidence for partial regulatory patterns observed in our multi-omics analyses. Our multi-omics SMR analysis prioritizes POLG and EARS2 as candidate genes genetically implicated in the susceptibility of overall CHD, and further adds evidence supporting a potential role for mitochondrial dysfunction in CHD etiology. These findings enhance our understanding of the complex genetic mechanisms of CHD and provide promising molecular targets for subsequent mechanistic investigation and therapeutic development.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.