Identifying differential interactions of potentially traumatic experiences with genetic risk for posttraumatic stress disorder

Abstract

ABSTRACT Background: Posttraumatic stress disorder (PTSD) occurs following potentially traumatic experiences, but not everyone who experiences trauma develops PTSD. Genetic factors play an important role in shaping how individuals respond to trauma, reflecting gene-environment interaction. An open and important question in PTSD genetics research is the extent to which gene-environment interactions vary across specific traumas. Objective: We aimed to compare gene-environment interaction effects across a broad range of self-reported potentially traumatic experiences across the lifespan. Method: We analysed existing data from two large UK cohorts: the UK Biobank and GLAD-EDGI-COPING (N = 144,702). PTSD symptoms were assessed using the six-item abbreviated PTSD Checklist. We examined eleven self-reported trauma exposures, including five childhood traumas and six adulthood traumas. We conducted gene-environment interaction analyses for each trauma at three levels of genetic specificity: polygenic risk scores, specific genes, and specific genetic variants. Results: Childhood traumas showed stronger associations with PTSD symptoms and greater gene-environment interactions than adulthood traumas on average. Childhood emotional and physical neglect also demonstrated greater gene-environment interactions than childhood abuse. Interaction patterns varied across genes and variants, with several leading PTSD-associated genes (e.g. ANAPC, FAM120A, SGCD) having particularly strong interactions with certain traumas. Several genes (DTX4, PSMD12, TYW3, ZNF660) demonstrated consistently stronger interactions across all childhood or all adulthood traumas. Differences in gene-environment interactions across traumas were not explained by variation in exposure rates, associations with PTSD symptoms, or gene-environment correlations. Conclusions: Our findings are consistent with differential gene-environment interactions on PTSD across potentially traumatic experiences, with those in childhood exhibiting the strongest interactions. To account for the moderating role of trauma type on genetic associations, genetic research on PTSD should incorporate detailed trauma exposure information, which may improve PTSD risk prediction and support more personalised prevention approaches.