Association between adverse childhood experiences and gastro-esophageal diseases later in life: A large-population cohort and Mendelian randomization study

Background: Adverse childhood experiences (ACEs) are widely recognized as associated with stress-associated digestive disorders, yet their comprehensive relationship with gastro-esophageal diseases as well as the potential mechanisms of depression remains underexplored. Methods: The prospective study included 133,638 participants aged 40-69 from UK Biobank with full information on ACEs, depression, and gastro-esophageal diseases. ACEs were retrospectively measured both as individual types (physical, emotional, and sexual abuse, and physical and emotional neglect) and cumulative scores of experienced types. Cox proportional hazards model was utilized to assess the association of ACEs with the overall and type-specific risks of diseases. Two-sample Mendelian randomization (TSMR) was conducted utilizing data from a genome-wide association study of ACEs (N = 185,414) to further examine the causal relationship. Mediation analysis was performed to quantify the role of depression. Results: During a median follow-up of 13.3 years, those who had a history of ACEs were observed with a 15 % higher overall risk of gastro-esophageal diseases (HR, 1.15; 95%CI, 1.12-1.19) and 10-25 % increased typespecific risks compared to unexposed participants. Among five individual types of ACEs, the association was more prominent for emotional abuse (1.22, 1.17-1.27) and sexual abuse (1.24, 1.18-1.30). TSMR analysis consistently reported positive associations between ACE and four subtypes of gastro-esophageal diseases. Depression was found to mediate 17.2 % (13.5 %, 24.0 %) of the aforementioned relationship. Conclusions: Our findings highlight the importance of early screening and intervention on ACEs to reduce the long-term risk of gastro-esophageal diseases, and stress the potential of depression as a ponderable indirect intervention target.