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Background: Major depressive disorder (MDD) is accompanied by alterations in grey matter volume. However, the biological processes associated with regional structural perturbations remain elusive. Methods: We applied integrative omics analysis to investigate specialized transcriptome signatures and translational determinants associated with regional grey matter variations in 2737 MDD patients relative to 3098 controls by summarizing the results from gene co-expression network analysis of Allen human brain transcriptome profiles in six donors, enrichment analysis of gene-sets and cellular structure from rodents and mediation analysis of BrainSpan proteome profile in six donors. Results: We found convergent alterations of grey matter volume in MDD were associated with transcriptome profiles enriched for synaptic transmission, metabolism, immune processes and transmembrane transport. Genes with abnormal expression in post-mortem tissue in MDD were also associated with transcriptome signatures. Further gene co-expression network and enrichment analysis of MDD-related genes in these signatures revealed the modules with higher neuronal expression were enriched in the medial temporal cortex and temporo-parietal junction with genes differentially associated with neuronal development and metabolism. Also, the modules with higher non-neuronal (e.g. astrocyte and oligodendrocyte) expression were concentrated in the rostral and dorsal anterior cingulate cortex and were separately associated with immune response and transmembrane transport. Moreover, proteins as the gene expression products mediated the association between transcriptome signatures and brain volume changes in the visual and dorsolateral prefrontal cortex. Conclusions: Our multidimensional analyses offer a novel approach to detect specific biological pathways that capture regional structural variations in MDD, which suggests structural endophenotypes associated with MDD. [ABSTRACT FROM AUTHOR]

Abstract Background Cognitive dysfunction is one of the most prominent characteristics of psychiatric disorders. Currently, the neural correlates of cognitive dysfunction across psychiatric disorders are poorly understood. The aim of this study was to investigate functional connectivity and structural perturbations across psychiatric diagnoses in three neurocognitive networks of interest: the default mode network (DMN), the frontoparietal network (FPN), and the salience network (SN). Methods We performed meta-analyses of resting-state functional magnetic resonance imaging whole-brain seed-based functional connectivity in 8298 patients (involving eight disorders) and 8165 healthy control subjects and a voxel-based morphometry analysis of structural magnetic resonance imaging data in 14,027 patients (involving eight disorders) and 14,504 healthy control subjects. To aid the interpretation of the results, we examined neurocognitive function in 776 healthy participants from the Human Connectome Project. Results We found that the three neurocognitive networks of interest were characterized by shared alterations of functional connectivity architecture across psychiatric disorders. More specifically, hypoconnectivity was expressed between the DMN and ventral SN and between the SN and FPN, whereas hyperconnectivity was evident between the DMN and FPN and between the DMN and dorsal SN. This pattern of network alterations was associated with gray matter reductions in patients and was localized in regions that subserve general cognitive performance. Conclusions This study is the first to provide meta-analytic evidence of common alterations of functional connectivity within and between neurocognitive networks. The findings suggest a shared mechanism of network interactions that may associate with the generalized cognitive deficits observed in psychiatric disorders. [ABSTRACT FROM AUTHOR]