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This study explores potential causal associations between mitochondrial\u2010related genes and AIDs using integrated multi\u2010omics evidence from Mendelian randomization (MR) and colocalization analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Summary\u2010level datasets from 10 common AIDs (303\u2009590\u2013456\u2009348 participants) and quantitative trait loci (QTL) at the DNA methylation, gene expression, and protein abundance levels (mQTL, eQTL, and pQTL, respectively; 1\u2009980\u201335\u2009559 participants), as well as mitochondrial DNA copy number (465\u2009809 participants), were analyzed. Instrumental variables were selected from cis\u2010acting variants near 1136 mitochondrial\u2010related genes with strong associations (<jats:italic>p<\/jats:italic><jats:sub>QTL<\/jats:sub>\u2009&lt;\u20095e\u201008). Summary\u2010data\u2010based MR (SMR) and Bayesian colocalization analyses were applied to identify causal effects, followed by validation assessments integrating multi\u2010omics SMR results.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Four Grade\u2010II mitochondrial genes were causally linked to multiple AIDs. <jats:italic>ATAD3A<\/jats:italic> (OR: 1.41; 95% CI: 1.13\u20131.76, <jats:italic>p<\/jats:italic><jats:sub>SMR<\/jats:sub>\u2009=\u20091.64e\u201003) and <jats:italic>TOP1MT<\/jats:italic> (OR: 1.42; 95% CI: 1.10\u20131.84, <jats:italic>p<\/jats:italic><jats:sub>SMR<\/jats:sub>\u2009=\u20094.60e\u201003) were strongly associated with multiple myositis, while <jats:italic>SND1<\/jats:italic> (OR: 1.08; 95% CI: 1.04\u20131.12, <jats:italic>p<\/jats:italic><jats:sub>SMR<\/jats:sub>\u2009=\u20094.05e\u201003) was linked to osteoarthritis. Notably, TOP1MT expression conferred protective effects against primary Sj\u00f6gren's syndrome (OR: 0.57; 95% CI: 0.35\u20130.95, <jats:italic>p<\/jats:italic><jats:sub>SMR<\/jats:sub>\u2009=\u20098.21e\u201003). Crucially, only <jats:italic>UQCRH<\/jats:italic> was identified with the same variant (rs41292543) exhibiting inverse effects on multiple myositis, including causal effects through cg11235697 methylation (OR: 1.56; 95% CI: 1.23\u20131.98, <jats:italic>p<\/jats:italic><jats:sub>SMR<\/jats:sub>\u2009=\u20093.02e\u201004) and protective effects through gene expression (OR: 0.83; 95% CI: 0.72\u20130.95, <jats:italic>p<\/jats:italic><jats:sub>SMR<\/jats:sub>\u2009=\u20092.78e\u201004).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings provide robust evidence of mitochondrial dysfunction's causal role in AIDs and identify potential pharmacological targets for treatment, offering new insights into precision medicine for AIDs.<\/jats:p><\/jats:sec>","DOI":"10.1111\/1756-185x.70383","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T04:46:06Z","timestamp":1754541966000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identification of Causal Effects of Mitochondrial Dysfunction on the Risk of Multiple Autoimmune Disorders: Multi\u2010Omics Mendelian Randomization and Colocalization Analyses"],"prefix":"10.1111","volume":"28","author":[{"given":"Jing","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Rheumatology The Second Affiliated Hospital of Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Pan","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Centers for Disease Control and Prevention  Hangzhou 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