Transcriptional substrates of brain structural and functional impairments in drug-naive first-episode patients with major depressive disorder

Background: Despite remarkable success in identifying genetic risk factors for depression, there are still open questions about the exact genetic mechanisms underlying certain disease phenotypes, such as brain structural and functional impairments. Methods: Comprehensive multi-modal neuroimaging meta-analyses were conducted to examine changes in brain structure and function in drug-naive first-episode patients with major depressive disorder (DF-MDD). Combined with the Allen Human Brain Atlas, transcriptome-neuroimaging spatial association analyses were performed to identify genes whose expression related to these brain structural and functional changes, followed by a range of gene functional signature analyses. Results: Meta-analyses revealed gray matter atrophy in the insula, temporal pole, cerebellum and postcentral gyrus, and a complex pattern of hyper-function in the temporal pole and hypo-function in the cuneus/precuneus, angular gyrus and lingual gyrus in DF-MDD. Moreover, these brain structural and functional changes were spatially associated with the expression of 1194 and 1733 genes, respectively. Importantly, there were com-monalities and differences in the two gene sets and their functional signatures including functional enrichment, specific expression, behavioral relevance, and constructed protein-protein interaction networks. Limitations: The results merit further verification using a large sample of DF-MDD. Conclusions: Our findings not only corroborate the polygenic nature of depression, but also suggest common and distinct genetic modulations of brain structural and functional impairments in this disorder.