Proteomic Biomarkers as Mediators in the Association Between Air Pollution and Incident Depression and Anxiety: Evidence From the UK Biobank

<b>Background:</b> The association between ambient air pollution and the onset of depression and anxiety has attracted significant scholarly interest; however, its underlying mechanisms remain elusive. <b>Objective:</b> The primary objective of this study is to assess the connection between air pollution and the onset of depression and anxiety, with a specific emphasis on uncovering the potential pathways influenced by high-dimensional proteomic markers. Design, setting, and participants: This prospective, nationwide population-based cohort study utilized data from the UK Biobank, incorporating an analysis of proteomic data from 38,301 participants. <b>Method:</b> Air pollution levels for particulate matter (PM) diameters of ≤2.5 μm (PM_2.5), ≤10 μm (PM₁₀), 2.5-10 μm (PM_coarse), nitrogen oxides (NO_x), and nitrogen dioxide (NO₂) were estimated in 2010. The depression and anxiety symptoms were assessed through self-report questionnaires at baseline and at the 7-year follow-up, and diagnoses were determined using ICD-9/10 codes from hospital records. Plasma proteomic data for 1463 proteins was measured using the Olink platform. A two-step regression approach was used to identify proteins associated with both air pollution and depression/anxiety. Mediation analysis was performed using the med4way method. <b>Results:</b> This longitudinal nationwide study leveraged the UK Biobank cohort to elucidate the protein-mediated effects of five major air pollutants on depression and anxiety. The findings identified 23 proteins mediating the risk of developing depression associated with air pollution, while no mediating proteins were found for anxiety. Additionally, the study discovered 38 proteins linked to the severity of anxiety related to air pollution and nine proteins connected to the severity of depressive symptoms. Notably, KEGG pathway analysis revealed significant associations with critical signaling cascades, such as the estrogen, IL-17, and pathways. Furthermore, STRING analysis underscored the shared roles of specific proteins, including EGFR, IL15, CCL2, and CCL20, in the context of air pollution-induced depression and anxiety, highlighting the involvement of immune-related processes and pathways. <b>Conclusion:</b> The findings of this large population-based cohort study provide proteomic evidence on the mediating protein associations between air pollution and the onset of depression. The results suggest that the immune system plays a significant role in the biological mechanisms linking air pollution to depression and anxiety.