FKBP5 genotype-dependent DNA methylation and mRNA regulation after psychosocial stress in remitted depression and healthy controls
Open accessAbstract
BACKGROUND: Polymorphisms in the FK506 binding protein 5 (FKBP5) gene have been shown to influence glucocorticoid receptor sensitivity, stress response regulation, and depression risk in traumatized subjects, with most consistent findings reported for the functional variant rs1360780. In the present study, we investigated whether the FKBP5 polymorphism rs1360780 and lifetime history of major depression are associated with DNA methylation and FKBP5 gene expression after psychosocial stress. METHODS: A total of 116 individuals with a positive (n = 61) and negative (n = 55) lifetime history of major depression participated in the Trier Social Stress Test. We assessed plasma cortisol concentrations, FKBP5 mRNA expression, and CpG methylation of FKBP5 intron 7 in peripheral blood cells. RESULTS: Genotype-dependent plasma cortisol response to psychosocial stress exposure was observed in healthy controls, with the highest and longest-lasting cortisol increase in subjects with the TT genotype of the FKBP5 polymorphism rs1360780, and healthy controls carrying the T risk allele responded with a blunted FKBP5 mRNA expression after psychosocial stress. No genotype effects could be found in remitted depression. CONCLUSIONS: The FKBP5 rs1360780 polymorphism is associated with plasma cortisol and FKBP5 mRNA expression after psychosocial stress in healthy controls but not in remitted depression. Preliminary results of the DNA methylation analysis suggest that epigenetic modifications could be involved.
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MDD studies show that FKBP5 expression is epigenetically elevated and associated with structural and functional alterations in brain regions involved in emotional processing.
“MDD studies show that FKBP5 expression is epigenetically elevated and associated with structural and functional alterations in brain regions involved in emotional processing”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [89]
The Introduction (page unavailable) says FKBP5 demethylation can upregulate its expression and reports differences in FKBP5 mRNA between depressed patients and controls. It does not establish that expression is epigenetically elevated in MDD or link FKBP5 expression to structural and functional changes in emotion-processing brain regions. The study measured methylation and mRNA in peripheral blood cells, not brain structure or function. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSome clinical studies using peripheral blood to examine DNA methylation changes in MDD corrected for cell composition.
“some clinical studies using peripheral blood to examine DNA methylation changes in MDD corrected for cell composition,101,102”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [102]
Changes in FKBP5 gene expression occur within 70 min.
“and changes in FKBP5 gene expression within 70 min [43].”
From Dynamic DNA methylation changes in the COMT gene promoter region in response to mental stress and its modulation by transcranial direct current stimulation (2021) · cites this paper as [43]
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- Authors
- Hohne, N., Poidinger, M., Merz, F., Pfister, H., Bruckl, T., Zimmermann, P., Uhr, M., Holsboer, F., & Ising, M.
- Affiliations
- HolsboerMaschmeyer NeuroChemie (Germany) (DE)
- Corresponding author
- Ising, M.
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-12-13
- Volume
- 18
- Issue
- 4
- Pages
- pyu087-pyu087
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- PMC
- PMC4360217
- OpenAlex
- W2133924917
- Cited by
- 74
- References
- 39
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 5 · 2021: 10 · 2020: 8 · 2019: 6 · 2018: 8 · 2017: 12 · 2016: 9 · 2015: 4
- FWCI
- 4.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, cc-by-nc)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Max-Planck-Gesellschaft
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- FKBP5, DNA methylation, psychosocial stress, major depressive disorder, remitted depression, plasma cortisol, glucocorticoid receptor, epigenetics, Trier Social Stress Test
- MeSH terms
- Tacrolimus Binding Protein 5, Adrenocorticotropic Hormone, Adult, Depressive Disorder, Major, Major Depressive Disorder, Female, Genotype, Humans, Hydrocortisone, Introns, Male, RNA, Messenger, Social Perception, Stress, Psychological, DNA Methylation, Polymorphism, Single Nucleotide, Tacrolimus Binding Proteins
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