Neuroticism increased risk of gastroesophageal reflux disease: Evidence from bidirectional Mendelian randomization

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder that severely reduces quality of life. Emerging data suggest that neuroticism, a personality trait associated with increased stress reactivity and sensitivity to physiological sensations, may contribute to GERD susceptibility. However, the causality remains unknown. A bidirectional Mendelian Randomization (MR) study was conducted to evaluate the causal link between neuroticism and GERD. Genetic data for neuroticism were sourced from the UK Biobank's genome-wide association study (GWAS) (n = 3,80,506), while GERD-associated genetic data were obtained from the FinnGen project (n = 4,17,314) for primary analysis and from the IEU Open GWAS database (n = 6,02,604) for replication and meta-analysis. Sensitivity analyses, including tests for heterogeneity and pleiotropy, were conducted to assess the robustness of causal inferences. Inverse-variance weighted (IVW) analyses revealed significant associations between certain neuroticism traits and an increased risk of GERD. The traits with the strongest associations were mood (odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.60, 2.53, P = 1.5 × 10-9), worry (OR = 1.59, 95% CI = 1.21, 2.07, P = .00078), and tense (OR = 1.70, 95% CI = 1.18, 2.44, P = .004). Weighted median and MR-Egger regression sensitivity analyses supported these findings. The results were validated in replication and meta-analysis. Reverse MR suggested GERD might influence traits like "WORRY" and "FED-UP"; however, these associations were non-significant after Bonferroni correction. Neuroticism traits, including mood, worry, and tense, may be associated with an increased risk of GERD. These findings highlight the potential role of psychological characteristics in GERD development and may provide insights into future risk assessment and management strategies for GERD.