Inflammatory proteins and depression: bidirectional analyses using UK Biobank and MR

Abstract Background Inflammatory processes have been implicated in depression, but whether inflammation precedes or follows the onset of depression remains unclear. We investigated the directionality and underlying mechanisms of this association using longitudinal epidemiological approaches, proteomic analyses and Mendelian randomization (MR). Methods In this prospective cohort study, we analysed plasma protein data from the UK Biobank and incorporated publicly available results from GWASs on plasma proteins and depression. For the plasma protein analyses, participants were classified into two groups: those who developed depression after the baseline assessments (n = 8,085), when plasma proteins were measured using the Olink assay, and those with a depression diagnosis before or at baseline (n = 6,076). Results Adjusted logistic and linear regression analyses identified proteins associated with future and prior depression. Of 762 inflammatory proteins, 270 were associated with future and 157 with prior depression after FDR correction. These were further analysed using MR. Two proteins had a potential causal association with depression, both passing MR sensitivity analyses. Conversely, depression was potentially causally associated with 42 proteins, of which 9 passed sensitivity analyses. Pathway enrichment analyses indicated that proteins linked to future depression were enriched in immune and leukocyte activation and leukocyte migration pathways, whereas those linked to prior depression were enriched in cytokine signalling, T-cell activation and interleukin-10 regulation. Conclusions These findings identify immune system-related proteins associated with both the development and presence of depression, suggesting that different inflammatory pathways may be activated depending on the direction of the association. This evidence may contribute to the identification of depression subtypes with inflammatory components and inform future therapeutic targets. Key messages • Inflammatory proteins show distinct biological signatures in future versus prior depression, suggesting direction-specific pathways linking inflammation and depression onset. • This study identifies immune system-related proteins that may contribute to the development of novel drug targets for depression prevention and treatment of its inflammatory components.