From mitochondrial dysfunction to frailty and sarcopenia: genetic evidence from multi-omics data via Mendelian randomization and colocalization.

Frailty and sarcopenia are age-related conditions linked to mitochondrial dysfunction, but their causal mechanisms remain poorly defined. This study aimed to identify mitochondrial-related genes causally associated with frailty and sarcopenia using comprehensive multi-omics approaches. We performed summary-data-based Mendelian randomization using genome-wide association study summary statistics for the frailty index and sarcopenia-related traits. Quantitative trait loci data for DNA methylation, gene expression, and plasma protein abundance were analyzed across 1136 mitochondrial-related genes. Colocalization analysis was applied to confirm shared causal variants. For frailty, GRPEL1 showed tissue-specific associations at methylation and expression levels (protective in blood: β = -.15, false discovery rate (FDR) = 1.5e-02; adverse in brain/muscle), while LRPPRC demonstrated consistent protective effects across tissues (β = -.05 to -.13, PPH4 > 0.93). For sarcopenia-related traits, GATM was associated with appendicular lean mass (ALM) across all omics levels with opposing tissue effects (negative in blood: β = -.03, FDR = 1.9e-09; positive in muscle), and ETFDH showed positive associations with ALM (β = .03, FDR = 1.4e-06). Additional genes included CPS1 and MMAB for frailty, NTHL1 and MTCH2 for grip strength, and TOMM70, BNIP3, TUFM for walking pace. Complete regulatory pathways were identified for GRPEL1 and GATM, linking methylation to expression to phenotype. This multi-omics study identified distinct mitochondrial genetic signatures for frailty and sarcopenia, with key genes including GRPEL1, LRPPRC, GATM, ETFDH, and others showing tissue-specific causal associations. These findings advance understanding of mitochondrial mechanisms in age-related functional decline and identify multiple therapeutic targets.