Brain morphology mediators of the link between childhood trauma and bipolar disorder: a large-scale international analysis

Childhood trauma is a risk factor 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 between childhood trauma and bipolar disorder might be mediated through brain morphology. Our goal was to determine whether cortical thickness, cortical surface or subcortical volume mediate the association between childhood trauma and bipolar disorder. We leveraged a large multi-site dataset from the ENIGMA Bipolar Disorder Working Group, comprising of 1,031 participants with bipolar disorder and 2,221 controls from 19 international cohorts. To identify brain morphology mediators of the association of childhood trauma and bipolar disorder, we used high-dimensional mediation analysis and validated our results using leave-one-site-out cross-validation and permutation testing for significance. 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], p<0.001). Significant mediators were hippocampal volume (0.004, 95% CI: [0.002, 0.005], p<0.001), medial orbitofrontal gray matter thickness (0.002, 95% CI: [0.002, 0.003], p<0.001), and superior frontal gyrus gray matter thickness (0.002, 95% CI: [0, 0.005], p<0.001). Our results show that the severity of childhood trauma exposure is 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 our etiologic understanding of bipolar disorder and could help to identify those at risk and enable the development of new interventions.