Importance: Childhood trauma is associated with increased risk for bipolar disorder, but the biological mechanisms of this association remain incompletely defined. Gray matter differences observed after trauma exposure overlap with those reported in bipolar disorder, suggesting that the association of childhood trauma with bipolar disorder might be mediated through brain morphology. Objective: To determine whether cortical thickness, cortical surface, or subcortical volume mediate the association of childhood trauma with bipolar disorder. Design, Setting, and Participants: This case-control study conducted a cross-sectional analysis of individuals with bipolar disorder and healthy controls from 19 international cohorts (Enhancing NeuroImaging Genetics Through Meta-Analyses ENIGMA Bipolar Disorder Working Group) from January 2010 to December 2022. Data were analyzed from January 2025 to January 2026. Exposures: The primary exposure was the severity of total childhood trauma assessed with the Childhood Trauma Questionnaire, with secondary analyses of 5 subscales (emotional neglect and abuse, physical neglect and abuse, and sexual abuse). Main Outcomes and Measures: The primary outcome was bipolar disorder diagnosis (case vs control). The primary measure was the mediation effects of childhood trauma on diagnosis via gray matter (75 bilateral-averaged cortical thickness, surface, and subcortical volume measures). The mediation pathway from severity of childhood trauma to bipolar disorder through brain morphology was specified a priori. High-dimensional mediation analysis, with leave-one-site-out cross-validation and permutation testing for significance (false discovery rate FDR), was conducted. Results: The final sample included 2221 healthy controls (mean SD age, 35.6 13.2 years; 1274 female 57%) and 1031 participants with bipolar disorder (mean SD age, 38.6 13.7 years; 579 female 56%). Severity of childhood trauma was directly associated with higher likelihood of having a bipolar disorder diagnosis (median coefficient, 0.841; 95% CI, 0.834-0.851; range, 0.776-0.893; FDR P < .001). Less than 1% of the association between childhood trauma and bipolar disorder was mediated by brain morphology. Statistically significant mediators were hippocampal volume (median coefficient, 0.004; 95% CI, 0.002-0.005; range, 0-0.008; FDR P < .001), medial orbitofrontal gray matter thickness (median coefficient, 0.002; 95% CI, 0.002-0.003; range, 0-0.004; FDR P < .001), and superior frontal gyrus gray matter thickness (median coefficient, 0.002; 95% CI, 0.002-0.003; range, 0-0.005; FDR P < .001). Conclusions and Relevance: This study found that severity of childhood trauma exposure was associated with bipolar disorder diagnosis in part through a smaller hippocampus, thinner cortex in the medial orbitofrontal gyrus, and thinner cortex in the superior frontal gyrus. The identification of this mechanistic pathway improves understanding of the disorder, could help to identify those at risk, and enable the development of new interventions.
Tozzi et al. (Wed,) studied this question.