دانلود رایگان مقاله انگلیسی اثرات متضاد مولکولی افسردگی در مردان و زنان - الزویر 2018

Abstract

Background: Major depressive disorder (MDD) affects women approximately twice as often as men. Women are three times as likely to have atypical depression, with hypersomnia and weight gain. This suggests that the molecular mechanisms of MDD may differ by sex. Methods: To test this hypothesis, we performed a large-scale gene expression meta-analysis across three corticolimbic brain regions, the dorsolateral prefrontal cortex, subgenual anterior cingulate cortex, and basolateral amygdala (N=26 men, 24 women with MDD and sex-matched controls). Results were further analyzed using a threshold-free approach, gene ontology, and cell type-specific analyses. A separate dataset was used for independent validation [N=13 MDD subjects/sex; 22 controls (13 males, 9 females)]. Results: Of the 706 genes differentially expressed in men with MDD and 882 genes differentially expressed in women with MDD, only 21 were changed in the same direction in both sexes. Notably, 52 genes displayed expression changes in opposite directions between men and women with MDD. Similar results were obtained using a threshold-free approach, where the overall transcriptional profile of MDD was opposite in men and women. Gene ontology indicated that men with MDD had decreases in synapse-related genes, whereas women with MDD exhibited transcriptional increases in this pathway. Cell type-specific analysis indicated that men with MDD exhibited increases in oligodendrocyte- and microglia-related genes, while women with MDD had decreases in markers of these cell types. Conclusions: The brain transcriptional profile of MDD differs greatly by sex, with multiple transcriptional changes in opposite directions between men and women with MDD.

Discussion

We report almost no overlap in transcriptional changes across corticolimbic brain regions in men and women with MDD, but instead opposite transcriptional changes. Our results suggest that men with MDD have decreases, but women with MDD have increases in synapse-related genes. Immune-related reductions characterized female MDD. Cell type-specific analysis suggests increases in oligodendrocyte- and microglia-specific genes in men with MDD, but decreases in markers of these cell types in women with MDD. Together, these findings point towards distinct, and even opposite molecular changes in MDD in men and women.

Our results are partially consistent with results from a recent publication reporting sex-specific changes in MDD (46). While we also found very little overlap in DE genes in men and women with MDD, our results indicate a high level of transcriptional overlap in genes changed in opposite directions. In fact, we used our statistical methods on the data generated by Labonte et al. (46) and found very similar, but unreported opposite transcriptional results. Brains used in the previous publication were from a different brain bank, supporting the generalizability of our findings. Here, we include results from the AMY, which is not included in Labonte et al. (46). Although consistent with our hypothesis, it is somewhat surprising that these sex-specific molecular changes in MDD were not reported previously. One reason might be because many previous postmortem brain analyses in MDD were performed in mostly (or only) men. Studies that included both sexes mostly did not have sufficient statistical power to stratify by sex, although a few prior reports have hinted at sex differences in MDD (see examples in the Introduction) We believe that our meta-analysis/regression approach gave us the statistical power to investigate larger-scale profiles of molecular changes occurring in the brains of men and women with MDD.