Integrative neuroimmunology reveals leukocyte-expressing PAX6 as a critical predictor of major depressive disorder.

Major depressive disorder (MDD) is a multifaceted psychiatric illness with profound global consequences. To illuminate its molecular underpinnings, we employed a genome-driven integrative systems neuroimmunology approach to analyze transcriptomic profiles from 3114 individuals (1877 MDD patients and 1237 controls). This analysis uncovered coordinated neuroimmune transcriptomic shifts, marked by altered expression of genes involved in innate immune regulation, suppression of inflammatory responses, and pathways related to sensory perception, visual system development, and synaptic signaling. These alterations were consistently observed in both peripheral blood leukocytes (PBLs) and brain regions implicated in MDD. Among 31 genes jointly dysregulated in blood and brain, four stood out as robust predictors of MDD in PBLs: NEGR1, PPP6C, SORCS3, and PAX6. Of these, PAX6, a gene previously linked to MDD by GWAS, also exhibited differential expression in the amygdala and was functionally enriched in pathways governing immune modulation, vesicle trafficking, and neurodevelopmental processes, such as neuronal fate determination. In contrast, NEGR1, PPP6C, and SORCS3 showed no significant changes in brain expression, suggesting a predominantly peripheral role. Importantly, these transcriptomic insights were reinforced in a murine model of chronic stress, where immunophenotyping revealed elevated PAX6 expression in peripheral myeloid cells. Together, these findings reveal a shared neuroimmune signature across the brain and immune system in MDD, highlighting PAX6 as a promising mechanistic link and potential biomarker for this disorder.