Sex-Specific Transcriptional Signatures in Human Depression

By B. Labonté, O. Engmann, Immanuel Purushothaman, C. Ménard, Junshi Wang, Chunfeng Tan, Joseph R. Scarpa, Gregory Moy, Y. Loh, M. Cahill and 18 more. Nature Medicine, 2017

678 citations recorded by the source corpus.

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.

Subfields: Aging, Behavioral Neuroscience, Physiology

View Paper: https://www.semanticscholar.org/paper/5ba342c5d9e8f2b342d90386d9223eacbc2dfade

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Behavioral Neuroscience

1. G. Sanacora
2. R. Duman
3. John H. Krystal

In Physiology

1. Daniel H. Geschwind
2. R. Duman

Citations in the corpus

• Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018, positive): “Of note, a nearly identical module was recently identified as a sex-specific transcriptional signature of major depression and stress susceptibility (64).”
• Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments (2019, background): “Moreover, they found convergence of these sex specific modules at the level of activity of excitatory neurons in the PFC that could underlie the observed convergence on depressive behaviors (Labonte et al., 2017).”
• Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024, background): “33 In addition, studies of drug gene interactions, transcriptional genes associated with the risk of MDD are also reported, such as D2 subtype of the dopamine receptor (DRD2) and fatty acid desaturase (FADS), 34 which may serve as promising new targets for therapeutic intervention points.”