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Nat Med. 2017 Sep;23(9):1102-1111. doi: 10.1038/nm.4386. Epub 2017 Aug 21.

Sex-specific transcriptional signatures in human depression.

Author information

1
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
2
Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
3
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
4
Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
5
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
6
Department of Psychiatry, McGill University, Montreal, Québec, Canada.
7
McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Québec, Canada.

Abstract

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.

PMID:
28825715
PMCID:
PMC5734943
DOI:
10.1038/nm.4386
[Indexed for MEDLINE]
Free PMC Article

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