Childhood trauma-related brain alterations in bipolar disorder: an ENIGMA-bipolar disorder study

Introduction: Childhood trauma is experienced by more than 50% of people with severe psychiatric disorders and is a risk factor for bipolar disorder (BD). Previous studies have investigated associations between childhood trauma, brain morphology, and the likelihood of developing BD. However, most prior studies have been conducted in small samples using heterogeneous methodologies (e.g., different brain imaging methods or childhood trauma assessments), resulting in inconsistent findings. Our study from the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder working group (ENIGMA-BD) aims to determine the impact of childhood trauma on brain morphology in BD, using the largest international sample of individuals with bipolar disorder assembled to date. Methods: Nineteen independent cross-sectional samples, including 1105 BD cases (56% females) and 2344 healthy controls (HCs; 57% females) were collated via ENIGMA-BD. Severity of childhood trauma was measured using the Childhood Trauma Questionnaire (CTQ) at all sites. Structural 3D T1-weighted brain MRI scans were processed using ENIGMA-standard FreeSurfer and quality control to derive measures of subcortical volumes (16 regions), cortical thickness and surface area (68 regions from the Desikan-Killiany atlas). Data were harmonised for potential site differences using ComBat. Linear regressions were used to determine the associations between BD diagnosis (BD versus HC), severity of childhood trauma (CTQ total score) and their interaction on brain morphology. Age, sex, and total intracranial volumes (for subcortical volume analyses only) were included as covariates. False-Discovery Rate correction (q