Microglial function interacts with the environment to affect sex-specific depression risk

Eamon Fitzgerald; Irina Pokhvisneva; Sachin Patel; Shi Yu Chan; Ai Peng Tan; Helen Chen; Patricia Pelufo Silveira; Michael J Meaney

doi:10.1016/j.bbi.2024.04.030

Microglial function interacts with the environment to affect sex-specific depression risk

Brain Behav Immun. 2024 Apr 25:119:597-606. doi: 10.1016/j.bbi.2024.04.030. Online ahead of print.

Authors

Eamon Fitzgerald¹, Irina Pokhvisneva², Sachin Patel², Shi Yu Chan³, Ai Peng Tan⁴, Helen Chen⁵, Patricia Pelufo Silveira⁶, Michael J Meaney⁷

Affiliations

¹ Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Canada; Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Canada. Electronic address: eamon.fitzgerald@mcgill.ca.
² Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Canada.
³ Translational Neuroscience Program, Singapore Institute for Clinical Sciences, Singapore.
⁴ Translational Neuroscience Program, Singapore Institute for Clinical Sciences, Singapore; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Diagnostic Imaging, National University Health System, Singapore; Brain - Body Initiative, Agency for Science, Technology & Research (A*STAR), Singapore.
⁵ Department of Psychological Medicine, KK Women's and Children's Hospital, Singapore; Duke-National University of Singapore, Singapore.
⁶ Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Canada; Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Canada; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁷ Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Canada; Translational Neuroscience Program, Singapore Institute for Clinical Sciences, Singapore; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Brain - Body Initiative, Agency for Science, Technology & Research (A*STAR), Singapore. Electronic address: michael.meaney@mcgill.ca.

PMID: 38670238
DOI: 10.1016/j.bbi.2024.04.030

Abstract

There is a two-fold higher incidence of depression in females compared to men with recent studies suggesting a role for microglia in conferring this sex-dependent depression risk. In this study we investigated the nature of this relation. Using GWAS enrichment, gene-set enrichment analysis and Mendelian randomization, we found minimal evidence for a direct relation between genes functionally related to microglia and sex-dependent genetic risk for depression. We then used expression quantitative trait loci and single nucleus RNA-sequencing resources to generate polygenic scores (PGS) representative of individual variation in microglial function in the adult (UK Biobank; N = 54753-72682) and fetal (ALSPAC; N = 1452) periods. The adult microglial PGS moderated the association between BMI (UK Biobank; beta = 0.001, 95 %CI 0.0009 to 0.003, P = 7.74E-6) and financial insecurity (UK Biobank; beta = 0.001, 95 %CI 0.005 to 0.015, P = 2E-4) with depressive symptoms in females. The fetal microglia PGS moderated the association between maternal prenatal depressive symptoms and offspring depressive symptoms at 24 years in females (ALSPAC; beta = 0.04, 95 %CI 0.004 to 0.07, P = 0.03). We found no evidence for an interaction between the microglial PGS and depression risk factors in males. Our results illustrate a role for microglial function in the conferral of sex-dependent depression risk following exposure to a depression risk factor.

Keywords: Depression; Genetics; Microglia; Psychiatric disorders; Risk factors; Sex differences.