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

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Funding for this study was provided through funding of the Depression Task Force of the Hope for Depression Research Foundation to Michael J Meaney. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for the GUSTO study was attained from the National Healthcare Group Domain Specific Review Board (NHG DSRB; D/2009/021 and B/2014/00411) and the SingHealth Centralized Institutional Review Board (CIRB; D/2018/2767 and A/2019/2406). Ethical approval for the ALSPAC study was granted by the ALSPAC Ethics and Law Committee and local research ethics committees (full list available at ). Ethical approval for the UK Biobank was obtained from the Northwest Multicentre Research Ethics Committee (REC reference 11/NW/0382), the National Information Governance Board for Health and Social Care and the Community Health Index Advisory Group. All participants provided informed written consent before data collection. The research in this manuscript was conducted under application number 41975. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data used in this manuscript are available dependent on successful application to the relevant cohort study