Uncovering plasma protein biomarkers linked to depression: A differential abundance analysis and Mendelian randomization using large-scale data

Plasma proteins are potential biomarkers and drug targets that offer insights into the biological underpinnings of depression; yet, evidence linking them to depression is scarce. To identify depression-linked proteins, we conducted differential protein abundance analysis (DPAA) on 2920 plasma proteins among 48,378 UK Biobank participants. Among DPAA-identified proteins, we conducted network and enrichment analyses to reveal possible biological mechanisms, and Mendelian randomization (MR) to explore causal links with depression using summary GWAS data for proteins ( N = 34,557) and depression (166,773 cases, 507,679 controls). The druggability assessment was also done to identify potential drug targets. Through DPAA, we identified 22 proteins associated with depression (P adjusted < 1.71 × 10 −5 ), with each SD in protein levels corresponding to an 11 %–27 % difference in depression risk. Most proteins were positively associated, whereas LRRN1, CNTN5, and ADAMTS8 showed inverse relationships. These proteins were enriched in carbohydrate binding, PI3K/AKT and NF-κB signalling, and cytokine–receptor interactions. Although MR suggested causal evidence for BTN3A2(P adjusted < 2.27 × 10 −3 ), colocalization indicated likely confounding by linkage disequilibrium (PPH 3 = 73.5 %). Other proteins (LGALS4, ADAMTS8, TNFRSF10B, CXADR, IGFBP4, and PRSS8) showed weak causal associations ( P < 0.05) with little colocalization support (PPH 4 ≤ 6.3 %). ADAMTS8 and TNFRSF10B were not replicated in non-Europeans. Many of these proteins were known druggable targets in diverse diseases. Several plasma proteins were associated with depression and enriched in immune-inflammatory pathways, though causal evidence was limited. Their druggability underscores the repurposing opportunities for immune dysregulations related to depression. • Identified 22 protein biomarkers associated with depression. • Many proteins are strongly enriched in immune and inflammatory pathways. • MR and colocalization suggested limited causal roles for BTN3A2 and other proteins. • Several of these proteins are druggable, highlighting their repurposing potential.