Immunophenotype-mediated effects of plasma proteins on major depressive disorder: A two-step Mendelian randomization...

The aim of this study was to investigate the mediating role of immune cells in the relationship between plasma proteins and the risk of major depressive disorder (MDD). Using a two-step, two-sample Mendelian randomization (MR) approach, we systematically assessed whether immune cells mediate the causal effects of plasma proteins on MDD. We found that eleven plasma proteins (TRABD, CACNB4, EDA, SAR1A, GLRX, COTL1, STOM, CRP, FGF22, and EDA2R) were positively associated with MDD risk, while one protein (SPTLC1) exhibited a negative association. Additionally, seven immune cell phenotypes-including CD14 on CD33dim HLA DR + CD11b + , memory B cells (% of B cells), IgD⁻ CD24⁻ % B cells, CD20 on B cells, CD27 on IgD⁺ CD24⁺, CD27 on IgD⁻ CD38dim, and CD62L on CD62L⁺ DCs-showed potential causal effects on MDD. Further mediation analysis revealed that three immune cell types mediated the effects of four plasma proteins on MDD: CD27 on IgD⁺ CD24⁺ cells mediated the effects of both COTL1 and RNF122 (mediation proportions: 5.13% and 4.50%, respectively); IgD⁻ CD24⁻ % B cells mediated the effect of EDA (12.1%); and CD62L on CD62L⁺ DCs mediated the effect of GLRX (-9.46%). The negative mediation proportion suggests a protective pathway. Sensitivity analyses supported the robustness of these findings.These results provide novel insights into immune-mediated mechanisms linking plasma proteins to MDD and may inform future research into targeted immunotherapeutic strategies.