CONVERGENT GENETIC ARCHITECTURE AND MOLECULAR PATHWAYS UNDERLYING COMORBIDITY BETWEEN OPIOID USE DISORDER AND OTHER PSYCHIATRIC DISORDERS

Background Opioid use disorder (OUD) is frequently comorbid with other neuropsychiatric disorders (NPDs), leading to worsening of both conditions. Despite decades of research, the molecular and genetic mechanisms underlying these comorbid conditions remain largely unclear. Methods We investigated the shared genetic/molecular architecture between OUD and four frequently co-occurring NPDs (major depressive disorder (MDD), schizophrenia (SCZ), bipolar disorder (BD), and post-traumatic stress disorder (PTSD)). We employed genetic correlation analysis, mendelian randomization (MR), transcriptome-wide association studies (TWAS), and pathway enrichment analysis across eleven brain tissues. Results Genetic correlation analysis revealed significant positive correlations between OUD and all four NPDs (rg = 0.25–0.51, p < 0.001). MR analyses provided evidence of a potential causal effect of genetically predicted OUD on all NPDs (p < 0.01). TWAS identified PRSS16 and ZSCAN9 genes significantly associated (FDR p < 0.05) with all five traits. Notably, AMT and P4HTM were identified as the most prevalent shared gene signals between OUD and MDD, and MAU2 between OUD-PTSD and OUD-SCZ. Pathway enrichment analysis revealed notable enrichment in endocrine, immune, and addiction-related pathways. Network topology analysis highlighted calcium signaling and glutamatergic synapse pathways as central hubs. Conclusion Our findings suggest a causal effect of genetically predicted OUD may contribute to increased risk of MDD, SCZ, BD, and PTSD. Convergent evidence revealed substantial shared genetic architecture and common molecular mechanisms involving calcium signaling and glutamatergic synapse pathways, underlying OUD-NPD comorbidity, highlighting potential therapeutic targets for intervention.