Identification of Mitochondria-Related Genes Associated with Stroke Risk Through Multi-omics Summary Data-Based MR Analysis

Mitochondrial dysfunction is linked to stroke risk, but the specific genes involved remain unclear. This study aimed to identify mitochondria-related genes associated with stroke. We performed summary data-based Mendelian randomization analyses using 1136 mitochondria-related genes, integrating methylation quantitative trait loci (mQTL), expression QTL (eQTL), and protein QTL (pQTL) data with stroke-related genome-wide association study (GWAS) results. Colocalization analyses were used to assess potential shared genetic signals, followed by validation in the UK Biobank (UKB) and FinnGen cohorts. We identified 115 CpG sites, 14 genes, and 5 proteins linked to stroke. Significant colocalization was found for 26 loci, including four genes (CYC1, MECR, NGRN, NLRX1) and two proteins (LONP1, MMUT). Validation in UKB confirmed seven CpG sites, with eight confirmed in FinnGen. MMUT protein abundance was negatively associated with stroke risk (OR = 0.730). PRDX3 showed a positive methylation-expression relationship (OR = 2.733; 95% CI, 2.004-3.727), with cg01126576 methylation (OR = 0.895; 95% CI, 0.819-0.978) and expression (OR = 0.909; 95% CI, 0.838-0.986) linked to reduced stroke risk, whereas higher protein abundance was associated with increased risk (OR = 1.472; 95% CI, 1.076-2.014). PRDX3 demonstrates contrasting associations at different molecular levels, while MMUT is validated as a stroke-associated protein, highlighting both as potential priorities for future mechanistic and therapeutic studies.