Dissecting the causal association between inflammation and post-traumatic stress disorder: A bidirectional Mendelian randomization study

Accumulating evidence showed a bidirectional association between post-traumatic stress disorder and inflammation. However, whether the association is causal remains unclear. We aimed to evaluate the causal relationships between inflammatory cytokines and post-traumatic stress disorder using two-sample bi-directional Mendelian randomization analysis.

Single nucleotide polymorphism from genome-wide association studies of inflammatory cytokines, C-reactive protein, and post-traumatic stress disorder (23,212 patients and 151,447 controls) was selected as instrumental variables. The causal associations were estimated by inverse variance weighting with sensitivity analyses using weighted median, MR-Egger, and MR-PRESSO methods.

We observed suggestive associations of genetically predicted interleukin-17 (IL-17) and RANTES with post-traumatic stress disorder. One standard deviation (SD) increase in genetically predicted level of IL-17 lowered the risk of post-traumatic stress disorder with an odds ratio (OR) of 0.902 (95 % CI = 0.828, 0.984, P = 0.02). One SD higher genetically predicted RANTES (CCL5) concentration increased post-traumatic stress disorder risk (OR = 1.067, 95 % CI = 1.005, 1.133, P = 0.032). However, we found no evidence of causal associations of post-traumatic stress disorder with the selected inflammatory cytokines and biomarkers. We observed no evidence supporting the presence of pleiotropy. The results of sensitivity analyses demonstrated the same directions and similar effect sizes as the primary findings.

Potential pleiotropy, possible weak instruments, and low statistical power limited our findings.

Inflammation was suggestively causally associated with the risk of post-traumatic stress disorder, and inflammatory cytokines had no downstream effect on post-traumatic stress disorder. Further studies are needed to explain the mechanisms of systemic inflammation and neuroinflammation in post-traumatic stress disorder.