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 gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across six brain regions. We overlap our human profiles with those from a mouse model, 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 in MDD, with limited overlap between males and females, an effect seen in both depressed humans and stressed mice. We identify key regulators of sex-specific gene networks underlying MDD and confirm their sex-specific impact as mediators of stress susceptibility. For example, downregulation of the female-specific hub gene Dusp6 in mouse prefrontal cortex mimicked stress susceptibility in females, but not males, by increasing ERK signaling and pyramidal neuron excitability. Such Dusp6 downregulation also recapitulated the transcriptional remodeling that occurs in prefrontal cortex of depressed females. Together our findings reveal marked sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder.
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We thank V. Vialou for his in vivo expertise, K. Gleason at The University of Texas Southwestern Medical Center and Josée Prud'homme and Danielle Cecyre at the Douglas Bell-Canada Brain Bank for their help with procuring human brain samples, and O. Jabado for his expert advice on RNA-seq. This work was funded by National Institute of Mental Health (NIMH) grants P50MH096890 and R01MH051399 and by the Hope for Depression Research Foundation (HDRF) to E.J.N. B.L. was supported by a Frederick Banting and Charles Best postdoctoral fellowship from the Canadian Institute for Health Research (CIHR) and now by a Research Chair in Molecular Neurobiology of Mood Disorders and a Fond de Recherche du Québec-Santé (FRQ-S) Junior 1 award.
The authors declare no competing financial interests.
Supplementary Figures 1–10 and Supplementary Tables 1, 5, 6 and 12. (PDF 2465 kb)
List of genes differentially expressed across brain regions in MDD versus control males. (XLSX 851 kb)
List of genes differentially expressed across brain regions in MDD versus control females. (XLSX 870 kb)
NanoString validation data in males and females. (XLSX 17 kb)
Statistics from the inter-region overlap analysis (Fisher's exact test) in human males with and without MDD. (XLSX 36 kb)
Statistics from the inter-region overlap analysis (Fisher's exact test) in human females with and without MDD. (XLSX 38 kb)
Summary statistics from Fisher's exact test overlap analyses. (XLSX 15 kb)
Summary of the gene ontology overlap analyses performed in males and females. (XLSX 398 kb)
List of genes differentially expressed between males and females at baseline (controls only). (XLSX 10698 kb)
Summary table of the gene network analysis results in male MDD. (XLSX 42 kb)
Summary table of the gene network analysis results in female MDD. (XLSX 47 kb)
Male MDD preservation analysis summary. (XLSX 25 kb)
Female MDD preservation analysis summary. (XLSX 31 kb)
List of genes differentially expressed across brain regions in stressed versus control males. (XLSX 398 kb)
List of genes differentially expressed across brain regions in stressed versus control females. (XLSX 508 kb)
Inter-species overlap analysis summary for gene differentially expressed in males and females. (XLSX 17 kb)
Inter-species overlap analysis summary for gene ontology terms enriched in males and females with MDD or stress. (XLSX 140 kb)
Gene ontology analysis summary for terms associated with MDD in humans (males and females) and stress in mice (males and females). (XLSX 17 kb)
Summary table for the correlation values of the top three covariates' principal components. (XLSX 8 kb)
List of gene differentially expressed across brain regions in males and females with MDD from the publicly available microarray validation cohort. (XLSX 14 kb)
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Labonté, B., Engmann, O., Purushothaman, I. et al. Sex-specific transcriptional signatures in human depression. Nat Med 23, 1102–1111 (2017). https://doi.org/10.1038/nm.4386
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