Major depressive disorder (MDD) has been shown to be associated with structural abnormalities in a variety of spatially diverse brain regions. However, the correlation between brain structural changes in MDD and gene expression is unclear. Here, we examine the link between brain-wide gene expression and morphometric changes in individuals with MDD, using neuroimaging data from two independent cohorts and a publicly available transcriptomic dataset. Morphometric similarity network (MSN) analysis shows replicable cortical structural differences in individuals with MDD compared to control subjects. Using human brain gene expression data, we observe that the expression of MDD-associated genes spatially correlates with MSN differences. Analysis of cell type-specific signature genes suggests that microglia and neuronal specific transcriptional changes account for most of the observed correlation with MDD-specific MSN differences. Collectively, our findings link molecular and structural changes relevant for MDD.

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Neuroimaging studies have uncovered the neural roots of individual differences in human general fluid intelligence (Gf). Gf is characterized by the function of specific neural circuits in brain gray-matter; however, the association between Gf and neural function in brain white-matter (WM) remains unclear. Given reliable detection of bloodoxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI) signals in WM, we used a functional, rather than an anatomical, neuromarker in WM to identify individual Gf. We collected longitudinal BOLD-fMRI data (in total three times,~11 months between time 1 and time 2, and~29 months between time 1 and time 3) in normal volunteers at rest, and identified WM functional connectomes that predicted the individual Gf at time 1 (n = 326). From internal validation analyses, we demonstrated that the constructed predictive model at time 1 predicted an individual's Gf from WM functional connectomes at time 2 (time 1 ∩ time 2: n = 105) and further at time 3 (time 1 ∩ time 3: n = 83). From external validation analyses, we demonstrated that the predictive model from time 1 was generalized to unseen individuals from another center (n = 53). From anatomical aspects, WM functional connectivity showing high predictive power predominantly included the superior longitudinal fasciculus system, deep frontal WM, and ventral frontoparietal tracts. These results thus demonstrated that WM functional connectomes offer a novel applicable neuromarker of Gf and supplement the gray-matter connectomes to explore brain-behavior relationships.

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