Integrated Transcriptomic and Mendelian Randomization Analyses Identify Novel Biomarkers of Depression and Diabetes Comorbidity

Objective: Type 2 diabetes mellitus (DM) and depressive disorder (DD) frequently co-occur; however, the mechanisms underlying their comorbidity remain insufficiently understood. Therefore, the aim of this study was to explore the immune dysregulation mechanisms involved in the pathogenesis of DM and DD. Transcriptomic profiling was integrated with Mendelian randomization (MR) to investigate the potential causal roles of immune-related genes in DM and DD, and identify candidate targets associated with their comorbidity. Method: MR analysis identified 21 candidate genes causally associated with DM and DD, including actin-related protein 2/3 complex subunit 2 (ARPC2) and autophagy-related protein 7 (ATG7), which were prioritized as key pathogenic genes. Functional enrichment and immune infiltration analyses further validated the MR results, confirming their association with immune-related pathways and immune cell infiltration. The expression of these genes was validated using in vitro and in vivo experiments. Results: Increased ARPC2 and ATG7 expression was associated with an elevated risk of DM-DD. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) indicated significant enrichment of immune-related pathways associated with these genes. Conclusion: ARPC2 and ATG7 were identified as candidate biomarkers of DM-DD comorbidity. These findings suggest that immune activation and autophagy-related pathways may contribute to the progression of DM-DD comorbidity.