Identification of Causal Effects of Mitochondrial Dysfunction on the Risk of Multiple Autoimmune Disorders: Multi-Omics Mendelian Randomization and Colocalization Analyses.

Background: Mitochondrial dysfunction has been implicated in the pathogenesis of autoimmune disorders (AIDs), but its causal role in disease susceptibility and progression remains unclear. This study explores potential causal associations between mitochondrial-related genes and AIDs using integrated multi-omics evidence from Mendelian randomization (MR) and colocalization analyses.

Methods: Summary-level datasets from 10 common AIDs (303 590-456 348 participants) and quantitative trait loci (QTL) at the DNA methylation, gene expression, and protein abundance levels (mQTL, eQTL, and pQTL, respectively; 1 980-35 559 participants), as well as mitochondrial DNA copy number (465 809 participants), were analyzed. Instrumental variables were selected from cis-acting variants near 1136 mitochondrial-related genes with strong associations (p < 5e-08). Summary-data-based MR (SMR) and Bayesian colocalization analyses were applied to identify causal effects, followed by validation assessments integrating multi-omics SMR results.

Results: Four Grade-II mitochondrial genes were causally linked to multiple AIDs. ATAD3A (OR: 1.41; 95% CI: 1.13-1.76, p = 1.64e-03) and TOP1MT (OR: 1.42; 95% CI: 1.10-1.84, p = 4.60e-03) were strongly associated with multiple myositis, while SND1 (OR: 1.08; 95% CI: 1.04-1.12, p = 4.05e-03) was linked to osteoarthritis. Notably, TOP1MT expression conferred protective effects against primary Sjögren's syndrome (OR: 0.57; 95% CI: 0.35-0.95, p = 8.21e-03). Crucially, only UQCRH was identified with the same variant (rs41292543) exhibiting inverse effects on multiple myositis, including causal effects through cg11235697 methylation (OR: 1.56; 95% CI: 1.23-1.98, p = 3.02e-04) and protective effects through gene expression (OR: 0.83; 95% CI: 0.72-0.95, p = 2.78e-04).

Conclusions: 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.