Investigation of sex- and age-specific effects of genetics risk for depression on peripheral biomarkers

Background: Polygenic risk for depression is associated with elevated white blood cell count (WBC), providing support for a pro-inflammatory causal mechanism of depression. However, the important roles of biological sex and age on depression and inflammation have not been accounted for in these analyses. Methods: We calculated polygenic risk scores for depression (PRSdep) in 362,074 individuals from the UK Biobank (aged 39-72, 53.7% female) and 22,965 individuals from the Canadian Longitudinal Study on Aging (CLSA; aged 45-86, 50.3% female). We tested for main effects of PRSdep, sex, and non-linear age, as well as their interactions, on 25 blood-based measures (i.e., from complete blood counts, metabolic and lipid panels, and inflammatory tests). Associations significant in both cohorts were carried forward for further sex-stratified and mediation modelling. Results: PRSdep was significantly associated with 13 biomarkers in the UK Biobank, with five replicating in the CLSA (WBC, granulocyte, and lymphocyte counts, and C-reactive protein and triglyceride levels), with standardized effect sizes ranging from {beta}=0.006 (C-reactive protein, p=7.50x10-4) to {beta}=0.03 (WBC, p=1.71x10-4). Sex-specific effects of PRSdep were observed for C-reactive protein levels (male; Stouffer's p=2.40x10-5) and triglyceride levels (female; Stouffer's p=5.19x10-3). Further differentiation was observed in the female subgroups based on post-menopausal status for WBC (Stouffer's p=3.83x10-3) and neutrophil/granulocyte (Stouffer's p=5.05x10-3) counts. Bi-directional mediation was also observed between all five biomarkers and a depression diagnosis, with up to 12.6% of the association between PRSdep and triglyceride levels mediated through depression. Conclusions: We have shown that effects of PRSdep on multiple peripheral biomarkers, beyond WBC, remain significant even when accounting for important interactions of biological sex and age, providing insight into the pro-inflammatory etiology of depression.