Different effect of adverse childhood experiences on white matter microstructure in major depression and bipolar disorder: moderating role of genetic liability

Adverse childhood experiences (ACEs) are risk factors for both major depressive (MDD) and bipolar disorder. ACEs have been associated with white matter (WM) alterations, but whether they have different effects in MDD and BD remains unclear. Polygenic risk scores (PRS) allow for an individual estimation of genetic liabilities for most psychiatric conditions. The aim of the present study was to characterize the effect of ACEs on WM microstructure in MDD and BD, testing a possible differential effect between the two diagnoses and investigating whether genetic liabilities might modulate this relation. 260 depressed inpatients (140 MDD and 120 BD, mean age 49.29 ± 10.60, F = 161) underwent 3T MRI scan and ACEs evaluation. MDD and BD PRS were calculated in a subset of patients. Significant ACEs x diagnosis interactions were found for several DTI metrics. Single group analyses showed widespread detrimental effects of ACEs on WM integrity in BD, and less pronounced effects in MDD. Significant moderating effect of BD PRS in the whole sample and in MDD specifically were found for the relation between ACEs, fractional anisotropy and radial diffusivity, with bipolar-like relations for higher values of BD PRS. The differential effect of ACEs on WM microstructure in the two diagnostic groups points towards putative differential pathophysiological routes through which childhood maltreatment affects the two conditions, while the identification of a BD PRS moderation on the whole sample and in MDD specifically sheds light on the causal relation between ACEs, diagnostic phenotype and DTI metrics, and provides a possible tool to disentangle MDD heterogeneity.