Multi-Omics and Mendelian-Randomization Investigation of Mitochondrial Genes in Irritable Bowel Syndrome

Introduction: This study aimed to explore potential causal relationships between mitochondria- related genes and irritable bowel syndrome (IBS) using integrative multi-omics analysis. Methods: Genome-wide association study data for IBS (1,480 cases and 454,868 controls) were integrated with mitochondrial gene data from DNA methylation quantitative trait loci, blood expression quantitative trait loci, and protein quantitative trait loci. Molecular trait associations with IBS were assessed through summary-based Mendelian randomization and co-localization analyses. Steiger filtering analysis was applied to identify causal directions, and candidate genes were independently replicated by two-sample MR in the FinnGen R11 cohort. Results: Three primary genes supported by multi-omics evidence—CASP3, GATM, and PDK1—were identified. Increased CASP3 methylation, expression, and protein were positively associated with IBS risk, indicating pro-apoptotic and pro-inflammatory mechanisms, whereas elevated GATM expression and protein were negatively associated, consistent with a protective role via creatine-mediated energy homeostasis. discussion: none Discussion: Additionally, 19 genes were classified as secondary evidence genes and 5 as tertiary evidence genes. Among these, genes such as ACAD10 and MSRA were validated using FinnGen data. Conclusion: This study represents the first application of multi-omics techniques to elucidate the relationship between mitochondrial genes and IBS. The findings indicate multiple candidate pathogenic genes and highlight the role of mitochondrial dysfunction in IBS pathogenesis. These findings offer new opportunities for the discovery of IBS biomarkers and the development of therapeutic strategies.