Mendelian randomisation and colocalisation reveal pleiotropic effects of the CD40/SLC12A5 locus on CD40 protein, depression, and immune disease

Abstract

Inflammatory pathways are implicated in depression, but the specific immune proteins and causal variants involved remain unclear. We tested potential causal relationships between 91 immune-related plasma proteins and depression using Generalised Summary-data-based Mendelian Randomisation (GSMR). We identified an association between CD40 protein levels and depression (OR: 0.95, 95% CI: 0.94–0.97, p  = 1.71 × 10 −11 ), explained largely by variants located near the CD40 gene. Follow-up colocalisation analyses indicated that the CD40 protein and depression associations in this region were attributable to different lead variants that are often inherited together, suggesting the GSMR association was confounded by correlated genetic signals. Analyses using gene expression data prioritised SLC12A5 , not CD40 , as the most likely gene driving the depression signal at this locus. SLC12A5 produces KCC2, a neuronal potassium-chloride transporter primarily expressed in the brain. Scanning a wide range of health traits showed the CD40 lead variant was predominantly associated with inflammatory disorders, while the depression lead variant was more strongly linked to psychiatric conditions. Overall, these results emphasise the value of combining Mendelian randomisation with colocalisation to separate shared biology from correlated signals in genomic regions where multiple traits map to the same locus (pleiotropy). In this case, plasma CD40 protein levels are unlikely to have a direct causal role in depression, whereas SLC12A5 -mediated effects may contribute to its underlying biology. Further functional and multi-omic studies are needed to clarify immune-brain interactions and identify therapeutic targets for depression.