Rachel Laattoe, Elina Hyppönen, David Stacey, Sarah Cohen‐Woods
Abstract Inflammatory pathways are implicated in depression, but the specific immune proteins and causal variants involved remain unclear. This study investigated potential causal relationships between 91 immune-related plasma proteins and depression using generalized summary Mendelian randomisation. We identified a robust association between CD40 protein levels and depression (OR: 0.95, 95% CI: 0.94 - 0.97, p = 1.71 × 10⁻¹¹), primarily driven by cis- acting variants. However, pairwise statistical colocalisation analyses of the CD40 locus indicated that CD40 protein and depression had distinct – though not independent – lead variants, suggesting the Mendelian randomisation signal was confounded by linkage disequilibrium. Analyses using expression quantitative trait locus data from the Genotype-Tissue Expression project prioritised SLC12A5 , not CD40 , as the most likely effector gene for depression risk at the locus. SLC12A5 encodes a potassium chloride co-transporter preferentially expressed in brain tissue, consistent with a role in depression. A phenome-wide association study showed the CD40 protein lead variant was primarily associated with inflammatory disorders, while the depression lead variant was more strongly linked to psychiatric conditions. Our results emphasise the importance of combining Mendelian randomisation with colocalisation analyses to disentangle pleiotropic effects at loci with complex genetic architecture, such as CD40/SLC12A5 . While plasma CD40 protein levels are unlikely to play a causal role in depression, SLC12A5 -mediated effects may contribute to its pathophysiology. These findings highlight the need for further functional and multi-omic studies to clarify immune-brain interactions and identify therapeutic targets for depression.