Abstract
BACKGROUND: Mitochondrial dysfunction has been demonstrated to be an important hallmark of sarcopenia, yet its specific mechanism remains obscure. In this study, mitochondrial-related genes were used as instrumental variables to proxy for mitochondrial dysfunction, and summary data for sarcopenia-related traits were used as outcomes to examine their genetic association. METHODS: A total of 1 136 mitochondrial-related genes from the human MitoCarta3.0 database were extracted. Genetic instruments for them were obtained from gene expression quantitative trait locus (eQTLs) study (n = 31 684). Aggregated data for sarcopenia-related traits including low hand grip strength (LHGS), appendiceal lean mass (ALM), and usual walking pace (UWP) were provided by large-scale genome-wide association studies (GWASs). We integrated eQTLs data with GWAS data to estimate genetic association between mitochondrial dysfunction and sarcopenia using summary-data-based Mendelian randomization (SMR) analysis. Additionally, we implemented colocalization analysis to strengthen their association. Finally, eQTLs data from skeletomuscular tissue (n = 706) was used to validate the primary findings. RESULTS: By integrating the analysis results from the 3 sarcopenia-related traits, 2 mitochondrial genes genetically associated with sarcopenia were identified, namely UQCC1 (tier 2 evidence) and ETFDH (tier 3 evidence). Specifically, elevated expression levels of UQCC1 increased LHGS risk (OR = 1.114; 95% CI, 1.078-1.152; P-FDR = 1.70 × 10-7), which matched the negative association between it and UWP (Beta = -0.015; 95% CI, -0.021 to -0.010; P-FDR = 6.70 × 10-5). Furthermore, elevated expression levels of ETFDH were found to be associated with both lower ALM (Beta = 0.031; 95% CI, 0.020-0.042; P-FDR = 1.41 × 10-6) and UWP (Beta = 0.013; 95% CI, 0.006-0.021; P-FDR = 0.029). Of note, consistent results were replicated in specific skeletomuscular tissues, further suggesting our findings were robust. CONCLUSIONS: Our analyses revealed the genetic association between 2 mitochondrial-related genes, ie, UQCC1 and ETFDH, and sarcopenia, highlighting the pivotal role of mitochondrial dysfunction driven by these genes in the pathogenesis of sarcopenia. Importantly, these candidate genes represent potential clinical drug targets for the treatment of sarcopenia.