What type of study is this?

This is a Mendelian randomization study (also classified as: Colocalization Analysis).

September 10, 2025International Journal of Rheumatic Diseases2 citations

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

JLJing LuoNanjing General Hospital of Nanjing Military Command JPJingjing PanZhejiang Center for Disease Control and Prevention GYGuanqun YaoShanxi Medical University

Key Points

Mitochondrial dysfunction was causally linked to multiple autoimmune disorders, offering new avenues for treatment.
Four mitochondrial genes were tied to autoimmunity, with specific genes showing strong associations with multiple myositis.
Analysis utilized summary-level data from over 300,000 participants, enhancing the robustness through multi-omics insights.
Findings highlight the potential of targeting mitochondrial dysfunction for advancing precision medicine in autoimmune conditions.

Abstract

ABSTRACT 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 QTL < 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 SMR = 1.64e‐03) and TOP1MT (OR: 1.42; 95% CI: 1.10–1.84, p SMR = 4.60e‐03) were strongly associated with multiple myositis, while SND1 (OR: 1.08; 95% CI: 1.04–1.12, p SMR = 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 SMR = 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 SMR = 3.02e‐04) and protective effects through gene expression (OR: 0.83; 95% CI: 0.72–0.95, p SMR = 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.

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