Contributions of Polygenic Risk and Disease Status to Gray Matter Abnormalities in Major Depression

Grey-matter abnormalities in depression are potentially attributable to some combination of trait, state, and illness-history factors. Here, we sought to determine the contributions of polygenic risk for depression, depressive-disease status, and their interaction to these grey-matter abnormalities. We conducted a cross-sectional comparison using a 2x3 factorial design examining effects of Polygenic Risk for depression (lower versus upper quartile) and Depression Status (never depressed, currently depressed, or remitted depressed) on regional grey-matter concentration and grey-matter volume. Participants were a subset of MRI-scanned UK Biobank participants comprising 2682 persons (1806 females, 876 males), algorithmically matched on 16 potential confounders. In females but not males we observed that elevated polygenic risk for depression was associated with reduced cerebellar grey-matter volume. This deficit occurred in salience- and dorsal-attention-network regions of the cerebellum and was associated with poorer performance on tests of attention and executive function but not fluid intelligence. Moreover, in currently depressed women, relative both to remitted depressed and never-disordered women, we observed grey-matter reductions in ventral and medial prefrontal, insular, and medial temporal regions. These state-related abnormalities remained when accounting for anti-depressant medication status. Neuroanatomical deficits attributed broadly to major depression are more likely due to an aggregation of independent factors. Polygenic risk for depression accounts for cerebellar structural abnormalities which, themselves, account for cognitive deficits observed in this disorder. Medial and ventral prefrontal, insular, and temporal cortex deficits constitute a much larger proportion of the aggregate deficit and are attributable to the depressed state.