Mitochondria-Related Genome-Wide Mendelian Randomization Identifies Putatively Genes for Chronic Fatigue

Chronic fatigue is a debilitating symptom linked to mitochondrial dysfunction which lacks comprehensive genetic insights. This study aims to investigate mitochondrial-related genes associated with chronic fatigue and explores therapeutic targets. We conducted summary-data-based Mendelian randomization (SMR) and Bayesian colocalization analyses using blood eQTL data (n = 31,684) and fatigue GWAS data (n = 449,019). Mitochondrial-related genes were sourced from MitoCarta3.0. Two-sample Mendelian randomization (TSMR) analysis and gene expression detection in rat models of fatigue were employed to enhance the robustness of our findings. Drug-gene interactions were screened via Drug SIGnatures (DSigDB) database and DrugBank database, followed by molecular docking and phenome-wide association study (PheWAS) for safety and pleiotropic effects evaluation. SMR identified nine mitochondrial-related genes, with AKAP10 (OR = 1.012) and MTHFD1L (OR = 1.027) showing robust colocalization and causal links to chronic fatigue. TSMR analysis also indicated significant causal relationships of AKAP10 (OR = 1.017, 95% CI = 1.011-1.023, p = 8.15e-08) and MTHFD1L (OR = 1.046, 95% CI = 1.002-1.091, p = 0.041) with chronic fatigue. Consistently, in fatigue model rats, the expression levels of Akap10 and Mthfd1l were significantly upregulated in both hippocampal and quadriceps tissues (p = 0.021, p = 0.003, p = 0.027, p = 0.001, respectively). Molecular docking revealed strong binding affinities (below -7.0 kcal/mol) between AKAP10, MTHFD1L and repurposed drugs (e.g., irinotecan, digoxin). PheWAS indicated that both AKAP10 and MTHFD1L exhibit no significant associations with other traits at the gene level. Mitochondria-related genes AKAP10 and MTHFD1L are promising targets for the treatment of chronic fatigue. Structural modification of existing drugs targeting these genes may lead to novel therapeutic approaches, which warrants further molecular and pharmacological validation to confirm their potential application in fatigue treatment.