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.

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Journal
Translational Psychiatry
Published
2025-11-29
DOI
https://doi.org/10.1038/s41398-025-03776-8
Primary Topic
Tryptophan and brain disorders
Type
article
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0.00

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article

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

Fernando Yuri Nery do Vale, Otávio Cabral-Marques, Rodrigo Juliani Siqueira Dalmolin, Rafael M. Rezende et al.
Translational Psychiatry
Tryptophan and brain disorders
article

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

Fernando Yuri Nery do Vale, Otávio Cabral-Marques, Rodrigo Juliani Siqueira Dalmolin, Rafael M. Rezende, Marília Garcia de Oliveira, Helder I. Nakaya, Elizabeth N Chung, Michael A. Wheeler, Igor Salerno Filgueiras, Dennyson Fonseca, Pedro Marçal Barcelos, Clement Hamani, Haroldo Dutra Dias, Gustavo Cabral‐Miranda, Renato Bortoloti, Lena F. Schimke, Anny Silva Adri, Ian Antunes Ferreira Bahia, Jinsu Lee, Adriel Leal Nóbile, Alexandre H. C. Marques
article en

Abstract

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.

Translational PsychiatryVol. 16(1)
Brigham and Women's Hospital (US), Sunnybrook Health Science Centre (CA), Harvard University (US), Universidade de São Paulo (BR), Hospital Israelita Albert Einstein (BR), Universidade Federal do Rio Grande do Norte (BR), D’Or Institute for Research and Education (BR), Inflammation Research Foundation (US)
Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Israel Science Foundation, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of Neurological Disorders and Stroke
Openalex Percentile: Top 61%
Tryptophan and brain disorders
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