Abstract Background The inflammatory markers C-reactive protein (CRP), interleukin-1 receptor antagonist (IL1-Ra), and interleukin-6 (IL-6) have been associated with depression risk in observational studies. The causal nature of these associations is unclear as conventional observational designs are susceptible to reverse causation and residual confounding. Bidirectional Mendelian randomization (MR) analysis uses genetic variants to proxy for risk factors to help elucidate the presence, magnitude, and direction of causal relationships between traits. Methods We performed bidirectional two-sample MR to examine causal associations between circulating CRP, IL1-Ra, and IL-6 and major depressive disorder (MDD) in 135,458 cases and 344,901 controls in the Psychiatric Genetics Consortium. Genetic instruments to proxy inflammatory markers and liability to MDD were constructed by obtaining single-nucleotide polymorphisms (SNPs) associated with these phenotypes in genome-wide association study meta-analyses. Wald ratios and inverse-variance weighted random-effects models were employed to generate causal effect estimates and various sensitivity analyses were performed to examine violations of MR assumptions. Results There was evidence supporting a causal effect of circulating IL-6 on risk of MDD (per natural-log increase: OR 0.85, 95% CI: 0.75-0.96, P =0.007). Higher circulating levels of IL-6 as influenced by variants in the IL6R gene region represent lower cellular binding of IL-6 to its receptor and therefore the present results suggest that IL-6 increases the risk of MDD. We found limited evidence supporting a causal effect of CRP (1.06, 95% CI 0.93-1.22; P=0.36) or IL1-Ra (OR 0.95, 95% CI: 0.87-1.03, P=0.20) on risk of MDD. Reverse direction MR analyses suggested limited evidence for a causal effect of genetic liability to MDD on any of the inflammatory markers examined. Conclusions These findings support a causal role of IL-6-related pathways in development of major depressive disorder and suggest the possible efficacy of interleukin-6 inhibition as a therapeutic target for depression.

Disentangling causal relationships between inflammatory markers and depression: a bidirectional Mendelian randomization analysis