Integrating Multi-Omics Data to Uncover Causal Links Between Mitochondria-Related Genes and Chronic Obstructive...

As a relatively common respiratory disease, chronic obstructive pulmonary disease (COPD) has a high incidence and mortality rate. Mitochondrial dysfunction has been implicated in COPD pathogenesis, but the causal genes and underlying molecular mechanisms remain unclear.

We performed a summary data-based Mendelian Randomization (SMR) study integrating summary data from genome-wide association studies (GWAS) with blood-based methylation (mQTL), expression (eQTL), and protein quantitative trait loci (pQTL) to identify mitochondrial-related genes causally associated with COPD. Significant findings were validated using two-sample MR, independent lung tissue transcriptomic data (GSE76925), and weighted gene co-expression network analysis (WGCNA) to assess transcriptional consistency and functional convergence.

Our integrative SMR and colocalization analyses identified 77 mitochondrial genes linked to COPD risk, including GPX1, TUFM, COQ5, BPHL, and NAGS. A methylation-to-expression regulatory cascade was observed, with hypermethylation at GPX1 cg24011261 associated with increased gene expression and higher COPD risk-despite its role as an antioxidant enzyme. Two-sample MR confirmed robust causal effects of GPX1, BPHL, TUFM and COQ5 expression on COPD. These findings were replicated in lung tissue: GPX1, COQ5, and TUFM were significantly upregulated in COPD patients (GSE76925). WGCNA revealed that these genes reside within a highly interconnected turquoise module strongly correlated with COPD status (r = 0.43, p < 0.001) and enriched in oxidative phosphorylation and mitochondrial energy metabolism pathways.

This study provides systematic genetic and transcriptomic evidence that mitochondrial-related genes, particularly GPX1 and TUFM, exert causal effects on COPD risk through regulatory cascades and coordinated network dysregulation. The convergence of genetic, epigenetic, and co-expression evidence underscores mitochondrial dysfunction as a central mechanism in COPD pathogenesis and highlights potential targets for future therapeutic development.