Exploring the causal biological association between mitochondrial genes and carotid plaques: A multiomics Mendelian...

To investigate the causal relationship between mitochondrial genes and the pathogenesis of carotid plaque (CP), a multiomics-integrated Mendelian randomization (MR) analysis was performed in this study.

Leveraging data from the McRae study, UK Biobank, eQTLGen Consortium, and decode database, we extracted mitochondrial gene QTLs at methylation, gene expression, and protein abundance levels as instrumental variables for MR and summary data-based Mendelian randomization (SMR) analyses. Multiomics evidence was classified by integrating MR, SMR, and colocalization results to investigate associations between mitochondria-related genes and CP.

Integration of multiomics data across mQTL, eQTL, and pQTL levels revealed 16 genes (GATM, CBR4, PGS1, PTPMT1, SDSL, SLC25A28, SPRYD4, TARS2, ACAT1, GRHPR, METAP1D, NIT2, ACSM2A, AGXT, TOP1MT, and CKMT2) that passed MR and SMR analyses. Among these, GATM demonstrated Tier 1 evidence, showing consistent causal associations with CP across all three levels. Specifically, methylation of cg10760299 in GATM was associated with lower GATM expression, increased protein levels, and a greater risk of CP. However, mtDNA copy number was not significantly associated with CP risk according to MR analysis.

This study identifies 16 mitochondrial genes with multiomics evidence linked to CP pathogenesis across genetic, methylation, and protein levels, highlighting the potential role of mitochondrial dysfunction in CP development and the potential of mitochondrial genes as biomarkers and therapeutic targets.