Integrative Multi-Omics Mendelian Randomization Reveals Oxidative Stress Mechanisms in Major Depressive Disorder, Bipolar Disorder, and Schizophrenia

Background: Oxidative stress (OS) has been widely implicated in pathophysiology of major psychiatric disorder. However, establishing robust causal links and delineating the specific molecular mechanisms involved continue to pose significant research challenges. Methods: We performed a multi-omics analysis focusing on 817 oxidative stress-related genes (OSGs) in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ). We applied summary data-based Mendelian randomization (SMR), integrating large-scale genome-wide association studies for MDD, BD, and SCZ with quantitative trait loci datasets from both blood and brain tissues, including measures of DNA methylation, gene expression, and protein abundance. Results: Multi-omics integration yielded supportive evidence across blood and brain tissues implicating ACE and ACADVL in SCZ, where genetically predicted increases in their methylation, expression, and protein abundance were associated with reduced disease risk. IGF1R was associated with bipolar disorder (BD) risk in blood-specific analyses. Brain-specific analyses further nominated ENDOG as a candidate gene for SCZ. Single-cell SMR indicated that increased ENDOG expression was associated with higher SCZ risk in astrocytes, CD4+ naïve T cells, CD8+ effector T cells, and natural killer cells, suggesting a potential immune–brain interaction. Conclusions: This study provides multi-level genetic evidence supportive of a potential causal role for specific OSGs in major psychiatric disorders. We identify ACE, ACADVL, IGF1R, and ENDOG as candidate genes for further investigation, offering insights into epigenetic and transcriptional mechanisms that could inform future research on therapeutic targets.