Associations Between Metabolic Syndrome, Depression, Plasma proteomics, and Neuroimaging Among Adults in the UK Biobank

Background Metabolic syndrome (MetS) is reported to be associated with increased incident depression. And previous research have linked depression development and plasma proteomic alterations. However, the association between MetS and depression, as well as the proteomic alterations or joint effects of depression related-proteins on brain macrostructure remain unclear. Methods This population-based retrospective cohort study leveraged data from 368,223 UK Biobank participants and 2911 plasma proteins profiled at baseline. MetS was defined as the presence of ≥3 of the following:elevated waist circumference; elevated levels of triglycerides, blood pressure, HbA1c; and reduced high-density lipoprotein cholesterol. Cox proportional hazard models were used to assess associations of MetS with depression. The least absolute shrinkage and selection operator(LASSO) regression was used to identify depression related proteins. The pearson correlation analysis was used to assess the relationship of identified proteins and brain structure. Then, mediation analysis was performed to uncover the potential mechanisms involving identified proteins and imaging-derived phenotypes. Results During a follow-up of 16.3 years, 13238 incident cases of depression were identified. MetS was associated with a increased risk of depression. We identified 93 proteins with significant associations with depression using LASSO regression, including proteins such as LDLR, FABP4, SMOC1, LPL, IGFBP1, and CA14. Additionally, dysregulation of the 93 proteins is correlated with brain regions implicated in depression, including the hippocampus and middle temporal. Further biological pathway enrichment analysis showed that most identified proteins were involved in cell adhesion, signaling receptor binding, and cholesterol metabolism, highlighted the pivotal roles of the immune response. Finally, mediation analysis revealed proteomic scores -neuroimaging have a strong mediating effect. Conclusions MetS was associated with a increased risk of depression, and we identified the proteomic signatures associated with MetS related- depression. These findings have crucial implications for understanding the intricate connections between MetS, depression, protein and brain health.