Integrating Mendelian randomization and multiple-trait colocalization to uncover cell-specific inflammatory drivers...

Immune-mediated diseases (IMDs) arise when tolerance is lost and chronic inflammation is targeted towards healthy tissues. Despite their growing prevalence, therapies to treat IMDs are lacking. Cytokines and their receptors orchestrate inflammatory responses by regulating elaborate signalling networks across multiple cell types making it challenging to pinpoint therapeutically relevant drivers of IMDs. We developed an analytical framework that integrates Mendelian randomization (MR) and multiple-trait colocalization (moloc) analyses to highlight putative cell-specific drivers of IMDs. MR evaluated causal associations between the levels of 10 circulating cytokines and 9 IMDs within human populations. Subsequently, we undertook moloc analyses to assess whether IMD trait, cytokine protein and corresponding gene expression are driven by a shared causal variant. Moreover, we leveraged gene expression data from three separate cell types (monocytes, neutrophils and T cells) to discern whether associations may be attributed to cell type-specific drivers of disease. MR analyses supported a causal role for IL-18 in inflammatory bowel disease (IBD) (P = 1.17 × 10-4) and eczema/dermatitis (P = 2.81 × 10-3), as well as associations between IL-2rα and IL-6R with several other IMDs. Moloc strengthened evidence of a causal association for these results, as well as providing evidence of a monocyte and neutrophil-driven role for IL-18 in IBD pathogenesis. In contrast, IL-2rα and IL-6R associations were found to be T cell specific. Our analytical pipeline can help to elucidate putative molecular pathways in the pathogeneses of IMDs, which could be applied to other disease contexts.