Sex-specific transcriptional signatures in human depression

Abstract

Summary Major depressive disorder (MDD) is a leading cause of disease burden worldwide. While the incidence, symptoms and treatment of MDD all point toward major sex differences, the molecular mechanisms underlying this sexual dimorphism remain largely unknown. Here, combining differential expression and weighted gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across 6 brain regions. We overlap our human profiles with those from a mouse model of chronic variable stress and capitalize on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility in males and females. Our results show a major rearrangement of transcriptional patterns, with male and female transcriptional profiles sharing very limited overlap, an effect seen in depressed humans and in stressed mice. We identify male and female hub genes and confirm their sex-specific impact as stress-susceptibility mediators. For example, downregulation of the female-specific hub gene DUSP6 in prefrontal cortex mimics stress susceptibility in females only by increasing ERK signaling and pyramidal neuron excitability. Such DUSP6 downregulation also recapitulates the transcriptional remodelling that occurs in PFC of depressed females. Together, our findings reveal dramatic sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder.

Sex-Specific Effects of Stress on Mood-Related Gene Expression

“…Recent studies which examined the molecular pathology of MDD report distinct molecular changes in men and women across several mesocorticolimbic brain regions [23, 46]. However, it is unclear which sex-related factors might drive this distinct MDD-associated pathology in the brain.…”

Sex-specific disease-associated modules for depression

“…The fact that CVS produces similar levels of depressive behaviors in both males and females demonstrates a limitation of this model. Nevertheless, transcript analysis in the Labonté et al 6 study shows very low overlap of DEGs (20–25%) between female and male mice exposed to CVS in the two brain regions examined (the vmPFC and nucleus accumbens). Importantly, the results also show substantial overlap of DEGs, modules, and hub genes in female mice exposed to CVS as compared to women with depression, as well as in male mice exposed to CVS relative to men with depression (for example, in the vmPFC, there are 251 up- or downregulated transcripts conserved in females, and 152 in males), demonstrating that the CVS-exposed mouse is a valid model system.…”

“…Despite these efforts, the heterogeneity of depression and the problems inherent in identifying illness-related gene variants have made it difficult to identify the molecular and neurobiological bases of depression, particularly, the greater incidence of the condition in women. In this issue, Labonté et al 6 use a bioinformatics approach 7,8 to demonstrate that depression is characterized by different disease-associated gene modules in the postmortem brains of women relative to those in men, and that these modules are conserved in mice. The findings define for the first time the notable sexually dimorphic gene-expression networks in key brain regions that are implicated in depression, and so will help to elucidate the pathophysiology of and potential avenues for treating depression, particularly in women.…”

Rapid-Acting Antidepressants: Mechanistic Insights and Future Directions

“…A recent study has started to explore differences in gene expression that could further explain the observed sexual dimorphism in MDD [77••]. The study reports on sex-specific disease-associated modules identified in postmortem brains of depressed male and female subjects.…”