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Cytokines are the signalling molecules that underlie inflammatory processes. Here, we performed genome-wide association study (GWAS) analyses of 47 circulating cytokines in up to 13,365 individuals to identify protein quantitative trait loci (pQTL). Applying a novel approach, we incorporated pQTL and expression quantitative trait loci (eQTL) data of 10,361 tissue samples in 635 individuals to identify biologically plausible genetic instruments to proxy the effect of cytokines. Using Mendelian randomization analysis, we explored the causal determinants of inflammatory cytokines, investigated inflammatory cascades and evaluated their effects on 20 diseases. We show evidence of body mass index (BMI), smoking and systolic blood pressure (SBP) being associated with inflammation, and specifically BMI affecting levels of active PAI-1, HGF, MCP1, sE-Selectin, sICAM1, TRAIL, IL6 and CRP. Our analysis highlights a key role of VEGF in influencing the levels of eight other inflammatory cytokines. Finally, we report evidence of sICAM affecting waist circumference and risk of major depressive disorder, evidence for TRAIL affecting the risk of cardiovascular diseases, breast and prostate cancer, and evidence for MIG affecting the risk of stroke. Overall, our results offer insight into inflammatory mediators of BMI, smoking and SBP, pleiotropic effects of VEGF, and circulating cytokines that increase the risk of cancer, cardiovascular, metabolic and neuropsychiatric diseases. All the studied cytokines represent pharmacological targets and therefore offer opportunities for clinical translation in diseases with inflammatory components.

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