Exploring mitochondrial genetic features in intervertebral disc degeneration through multi-omics integration analyses

The mitochondrial genetic basis of intervertebral disc degeneration (IVDD) remains incompletely understood. This study employed multi-omics Mendelian randomization (MR) analysis to investigate the potential mitochondrial-related genetic mechanisms underlying IVDD. Using two-sample MR, we integrated and analyzed multi-omics quantitative trait loci, encompassing methylation, expression, protein abundance, and mitochondrial DNA, from genome-wide association studies (GWAS). Genetic associations with IVDD were obtained from the FinnGen study for discovery and the GWAS Catalog database for validation, with Steiger filtering and co-localization analysis further performed to strengthen causal inference. Additionally, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and drug prediction analyses were comprehensively employed to identify potential therapeutic targets. Our multi-omics evidence identified 23 genes, among which 5 genes (glycine amidinotransferase [GATM], SLC25A13, acyl-CoA dehydrogenase short [ACADS], TSFM, and ATP23) showed tier 1 evidence for IVDD, with GATM demonstrating the strongest support. MR analysis revealed that a higher level of GATM was associated with a reduced risk of IVDD (odds ratio: 0.934, 95% confidence interval, 0.887-0.983). Furthermore, 15 drugs targeting GATM were identified, with HYDRONIDONE completing molecular docking. Through the integration of multi-omics data, we identified 5 promising therapeutic targets for IVDD, with GATM exhibiting the most consistent multi-omics signal, and discovered 15 drugs targeting GATM and 11 drugs targeting ACADS.