Microglial function moderates the relation between depression risk factors and depression outcomes across the life course in females

Abstract

Background Depression has an enormous socio-economic burden and is twice as common in women compared to men. Microglia are exceptionally responsive to environmental stimuli and their phenotype differs substantially by sex. We hypothesized microglial function would moderate the relation between depression risk factors and depressive outcomes in a sex-specific manner. Methods We 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 fetal (GUSTO; N=239-315, and ALSPAC; N=928-1461) and adult periods (UK Biobank; N=54753-72682). We stratified our analyses by sex and tested the interaction effects of these PGS with prenatal maternal depression symptoms and adult stressors, well-characterized depression risk factors. We used internalizing (early childhood) or depressive symptoms (late childhood and adulthood) as outcomes. Results The fetal microglia PGS moderated the association between maternal prenatal depressive symptoms and female offspring internalizing symptoms at 4 (GUSTO; beta=-0.25, 95%CI -0.44 to -0.06, P=0.008) and 7 years (GUSTO; beta=-0.16 , 95%CI -0.318 to -0.008, P=0.04), and depressive symptoms at 8.5-10 years (GUSTO; beta = -0.15, 95%CI = -0.25 to -0.03, P= 0.01) and 24 years (ALSPAC; beta=0.1, 95%CI 0.008 to 0.19, P=0.03). The adult microglial PGS moderated the relation 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. There were no significant interactions in males. Conclusion Our results illustrate an important role for microglial function in the conferral of sex-dependent depression risk.