Shared Blood Transcriptomic and Pathway Signatures in Major Depression, Generalized Anxiety, and Obsessive–Compulsive Disorder: A Systems‐Level Study

Major depressive disorder (MDD), generalized anxiety disorder (GAD), and obsessive-compulsive disorder (OCD) frequently co-occur and share overlapping symptomatology. This in silico study systematically investigated shared transcriptomic signatures and biological pathways using peripheral blood expression data. Differential expression analysis revealed 13 genes commonly dysregulated in at least two disorders, including CNTNAP3, PROK2, S100P, HLA-DPB1, and IRAK3. Correlation patterns uncovered disorder-specific rewiring of gene-gene networks, with polarity shifts and strength alterations particularly involving EIF5A2 and CNTNAP3B in MDD and OCD. Functional enrichment revealed convergence in neurotransmission, synaptic regulation, immune signaling, and metabolic pathways. Five biological pathways, including "defense response to bacterium" (GO-BP), "cytokine signaling in the immune system," "TCR signaling," and "neutrophil degranulation" (Reactome), and "leishmaniasis" (KEGG), were enriched across all three disorders, alongside multiple overlaps in GO-MF and GO-CC domains. Protein-protein interaction mapping revealed ribosomal hub dominance in OCD and immune/inflammatory node centrality in MDD and GAD. A panel of 21 secreted dysregulated genes in MDD, validated for ELISA detection, demonstrated robust classification power (AUC > 0.70). Drug-gene interaction analysis identified four downregulated compounds, carbamazepine, flupirtine, indomethacin, and doxorubicin hydrochloride, shared across all three disorders, suggesting therapeutic repurposing potential. These findings highlight shared immunometabolic dysregulation and nominate blood-based biomarkers and pharmacological targets applicable across psychiatric diagnostic categories.