Genetic causal effects of multi-site chronic pain on post-traumatic stress disorder: Evidence from a two-sample, two-step Mendelian randomization study

Background: Existing evidence supports a correlation between multi-site chronic pain and post-traumatic stress disorder (PTSD), but it is yet to be determined if this correlation is causal and in what direction the causation works. Methods: Applying two-sample Mendelian randomization (MR) analysis to data from available genome-wide association studies in populations of European ancestry, we estimated the causal association between multisite chronic pain and no pain versus PTSD. Moreover, we used multivariable and mediation MR analysis to assess the mediating effects of 13 lifestyle factors or diseases on the causal relationship between multi-site chronic pain and PTSD. The MR analyses were mainly conducted with the inverse variance weighted (IVW) method, followed by various sensitivity and validation analyses. Results: Multi-site chronic pain dramatically increases the risk of developing PTSD (odds ratio [OR]IVW = 2.39, 95 % confidence interval [CI] = 1.72-3.31, p = 2.10 x 10- 7), and no pain significantly reduces the risk of developing PTSD (ORIVW = 0.12, 95 % CI = 0.05-0.30, p = 3.14 x 10-6). Multivariable MR found that 13 potential confounding factors do not influence the causal effect of multi-site chronic pain on PTSD. Moreover, body mass index (BMI) (6.98 %), educational attainment (8.79 %), major depressive disorder (MDD) (36.98 %) and insomnia (27.25 %) mediate the causal connection between multi-site chronic pain and PTSD. Conclusion: Overall, individuals with multi-site chronic pain may be at a higher risk of developing PTSD, and this risk is partially influenced by the pathways involving BMI, educational attainment, MDD, and insomnia. These factors offer potential targets for therapeutic interventions.