AbstractObjectiveEpidemiological studies revealed an unestablished association between neuroticism and posttraumatic stress disorder (PTSD) and we conducted mendelian randomization (MR) analyses to examine whether neuroticism clusters of worry, depressed affect, and sensitivity to environmental stress and adversity (SESA) were involved in the development of PTSD.MethodWe obtained data on three neuroticism clusters, PTSD, and nine other psychiatric disorders from genome‐wide association studies summary statistics and employed univariable, multivariable, and mediation MR analyses to explore causal associations among them.ResultsNeuroticism clusters were linked with PTSD (depressed affect (odds ratio [OR]: 2.94 [95% confidence interval: 2.21–3.92]); SESA (2.69 [1.95–3.71]; worry (1.81 [1.37–2.99])). Neuroticism clusters were also associated with psychiatric disorders, with the depressed effect on panic disorder (PD) (2.60 [1.14–5.91]), SESA on anorexia nervosa (AN) (2.77 [1.95–3.94]) and schizophrenia (2.55 [1.99–3.25]), worry on major depressive disorder (MDD) (2.58 [2.19–3.05]). In multivariable MR, only the SESA‐PTSD association remained (2.60 [2.096, 3.107]) while worry‐PTSD and depressed affect‐PTSD associations attenuated to nonsignificance. Mediation MR analyses suggested that PD mediated 3.76% of the effect of depressed effect on PTSD and AN mediated 10.33% of the effect of SESA on PTSD.ConclusionDelving deeper into neuroticism clusters, we comprehensively understand the role of neuroticism in PTSD.