ObjectiveTo investigate the relationship between neuroticism and functional gastrointestinal disorders using Mendelian randomized (MR). MethodsBased on the genome-wide association study data of neuroticism and 2 functional gastrointestinal disorders, i.e., functional dyspepsia (FD), and irritable bowel syndrome (IBS), appropriate single nucleotide polymorphisms (SNP) were extracted as instrumental variables, and inverse variance weighted (IVW) was applied as the main analysis method, and sensitivity analyses were performed by Cochran’s Q test, MR-PRESSO test, MR-Egger intercept, and leave one out analysis. Further two-step MR analyses were performed to examine the mediating effects of coffee intake, alcohol consumption, smoking, depression. ResultsThe univariable MR analysis showed that genetically determined neuroticism was positively causally associated with the risk of developing FD and IBS (FD: OR=1.448, 95%CI 1.057 to 1.983, P=0.021; IBS: OR=1.705, 95%CI 1.210 to 2.403, P=0.002). Cochran's Q-test, MR-Egger intercept, MR-PRESSO did not observe significant heterogeneity or horizontal pleiotropy. Leave-one-out analyses also did not find a large effect of individual SNPs on the overall results. Multivariable MR analyses showed that the association between neurotic personality and elevated risk of FD and IBS prevalence persisted even after adjusting for other confounders. Further two-step MR mediation analyses revealed that depression partially mediated this effect, with mediation proportions of 59.41% (95%CI 5.69% to 113.12%) and 67.53% (95%CI 31.55% to 103.51%), respectively. ConclusionThere is a degree of causal association between neuroticism and FD and IBS, and depression may play an important mediating role in this association.