White matter tract integrity is reduced in depression and in individuals with genetic liability for depression

Background While major depression has been linked to changes in white matter architecture, it remains unclear whether risk factors for depression are directly associated with these alterations. We re-examined white matter fiber tracts in individuals with depressive symptoms and investigated the connection between genetic and environmental risk for depression and structural changes in the brain. Methods We included 17,183 participants from the UK Biobank imaging cohort, with depression status and adverse life experience based on questionnaire data and genetic liability for depression quantified by polygenic scores. The integrity of 27 white matter tracts was assessed using mean fractional anisotropy derived from diffusion MRI. Results White matter integrity was reduced in individuals suffering from depressive symptoms, particularly in thalamic and intracortical fiber tracts, independent of current symptom status. In a group of healthy non-depressed individuals, increasing genetic risk as well as increasing environmental risk was associated with reduced integrity in relevant fiber tracts, particularly in thalamic radiations. This association was stronger than expected based on statistical dependencies between samples, as confirmed by subsequent in-silico simulations and permutation tests. Conclusion White matter alterations in thalamic and association tracts are associated with depressive symptoms and with genetic risk for depression in unaffected individuals, suggesting an intermediate phenotype at the brain level.