Sex-specific transcriptional signatures in human depression
Open accessAbstract
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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In stress-related psychiatric disorders, there are sex-associated differences in incidence, symptoms and treatment response.
“In stress-related psychiatric disorders, there are sex-associated differences in incidence, symptoms and treatment response (268).”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [268]
The Introduction reports sex differences in the likelihood of developing major depressive disorder (MDD), symptom severity and presentation, and antidepressant treatment response. The claim extends those findings from MDD to stress-related psychiatric disorders generally, which this passage does not establish. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDepression is more common in females than males.
“Similarly, depression is more common in females than males (268).”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [268]
A nearly identical module was recently identified as a sex-specific transcriptional signature of major depression and stress susceptibility.
“Remarkably, a nearly identical module was recently identified as a sex-specific transcriptional signature of major depression and stress susceptibility (64).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [64]
A recent paper reported distinct transcription signatures in multiple brain areas between male and female MDD patients.
“A very recent paper reported distinct transcription signatures in multiple brain areas between male and female MDD patients, 26”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [26]
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“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.”
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- Authors
- Labonté, B., Engmann, O., Purushothaman, I., Menard, C., Wang, J., Tan, C., Scarpa, J. R., Moy, G., Loh, Y.-H. E., Cahill, M., Lorsch, Z. S., Hamilton, P. J., Calipari, E. S., Hodes, G. E., Issler, O., Kronman, H., Pfau, M., Obradovic, A. L. J., Dong, Y., Neve, R. L., Russo, S., Kasarskis, A., Tamminga, C., Mechawar, N., Turecki, G., Zhang, B., Shen, L., & Nestler, E. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- University of Pittsburgh (US)
- The University of Texas Southwestern Medical Center (US)
- Massachusetts Institute of Technology (US)
- Douglas Mental Health University Institute (CA)
- Corresponding author
- Nestler, Eric J
- ORCID
- Engmann, Olivia
- Wang, Junshi
- Tan, Chunfeng
- Scarpa, Joseph R
- Loh, Yong-Hwee E
- Cahill, Michael
- Lorsch, Zachary S
- Hamilton, Peter J
- Calipari, Erin S
- Hodes, Georgia E
- Issler, Orna
- Kronman, Hope
- Dong, Yan
- Neve, Rachael L
- Russo, Scott
- Kasarskis, Andrew
- Tamminga, Carol
- Mechawar, Naguib
- Turecki, Gustavo
- Zhang, Bin
- Shen, Li
- Nestler, Eric J
- Venue
- Nature Medicine
- Published
- 2017-08-21
- Volume
- 23
- Issue
- 9
- Pages
- 1102-1111
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5734943
- OpenAlex
- W2746917316
- Cited by
- 748
- References
- 135
- Citations by year
- 2026: 65 · 2025: 84 · 2024: 114 · 2023: 90 · 2022: 73 · 2021: 101 · 2020: 76 · 2019: 81 · 2018: 57 · 2017: 7
- FWCI
- 42.21
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-04-01)
- Open access
- green
- europepmc.org
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1s10od018522-01)
- National Institute of Mental Health (R21MH099562, R01MH090264, F30MH110073, P50MH096890, T32MH096678, F30MH106293, R01MH051399, R01MH104559, T32MH087004)
- National Institute on Drug Abuse (R21DA044538, R01DA034856, R01DA040620, R37DA023206)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- major depressive disorder, sex differences, sexual dimorphism, gene expression signatures, gene co-expression network, chronic variable stress, DUSP6, ERK signaling, prefrontal cortex, stress vulnerability, brain regions
- MeSH terms
- Adult, Aged, Animals, Brain, Cerebral Cortex, Major Depressive Disorder, Depressive Disorder, Major, Disease Models, Animal, Female, Hippocampus, Humans, Immunohistochemistry, Male, Middle Aged, Nucleus Accumbens, Sex Characteristics, Sex Factors, Stress, Psychological, Blotting, Western, Down-Regulation, Case-Control Studies, Prefrontal Cortex, Sequence Analysis, RNA, Pyramidal Cells, Patch-Clamp Techniques, Mice, Transcriptome
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