Sex-dependent association of DNA methylation of HPA axis-related gene FKBP5 with obsessive-compulsive disorder
Abstract
Aims Although hypothalamic-pituitary-adrenal (HPA) axis dysregulation in obsessive-compulsive disorder (OCD) has been reported, epigenetic changes in HPA axis-related genes have not been well studied in OCD. The present study investigated whether the epigenetic regulation of FK506-binding protein 51 gene (FKBP5) intron 7 is associated with OCD status in each sex. In addition, relationships among the DNA methylation levels of FKBP5 intron 7, OCD status and early-life trauma were explored.Methods A total of 267 patients with OCD and 201 controls aged between 18 and 40 years were recruited. Demographic and clinical assessment, FKBP5 rs1360780 genotyping, and pyrosequencing of FKBP5 intron 7 were conducted. DNA was extracted from peripheral blood leucocytes. First, multivariate analysis of covariance for differential DNA methylation levels between OCD patients and controls was conducted with adjustment for FKBP5 rs1360780 genotype, early-life trauma, depressive symptoms, and age as covariates in each sex. Next, path analysis was conducted to determine the mediation effects of DNA methylation levels of FKBP5 between early-life trauma and OCD status. In addition, sensitivity analyses for medication and lifetime major depression were also performed.Results DNA methylation at the FKBP5 intron 7 CpG site was significantly lower in men with OCD, compared to controls (mean difference -1.33%, 95% CI -2.11 to -0.55, p < 0.001). The results remained significant for drug naïve or free subjects (mean difference -1.27%, 95% CI -2.18 to -0.37, p = 0.006, in men) and for subjects without lifetime major depressive disorder (mean difference -1.60%, 95% CI -2.54 to -0.66, p < 0.001, in men). The mediation effect of DNA methylation levels was not significant between early-life trauma and OCD status.Conclusion These findings suggest that epigenetic factors of HPA axis-related gene FKBP5 may play a role in the pathogenesis of OCD. Further studies are needed to determine how altered DNA methylation of FKBP5 intron 7 and HPA axis function are involved in OCD.
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In OCD, reduced DNA methylation at the FKBP5 intron 7 CpG site has been reported in male patients relative to controls.
“In OCD, reduced DNA methylation at the FKBP5 intron 7 CpG site has been reported in male patients relative to controls”
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 [91]
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- Authors
- Seo, J. H., Kim, S. T., Jeon, S., Kang, J. I., & Kim, S. J.
- Affiliations
- Yonsei University (KR)
- Corresponding author
- Kim, Shin Tae
- Kang, Jee In
- Kim, Se Joo
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2023-12
- Volume
- 158
- Pages
- 106404
- ISSN
- 0306-4530 (ISSN-L)
- OpenAlex
- W4386997621
- Cited by
- 11
- References
- 76
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 1
- FWCI
- 3.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Research Foundation of Korea (2021M3E5D9025022, RS-2023-00209077, 2019 R1A2C1084611)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Social Sciences › Psychology › Clinical Psychology › Psychoanalysis and Psychopathology Research
- Keywords
- obsessive-compulsive disorder, FKBP5, DNA methylation, hypothalamic-pituitary-adrenal axis, sex differences, intron 7, early trauma, epigenetics, depression, gene-environment interaction, drug-naive patients, major depressive disorder, peripheral blood leukocytes
- MeSH terms
- Adolescent, Adult, Depressive Disorder, Major, Major Depressive Disorder, Humans, Hypothalamo-Hypophyseal System, Male, Obsessive-Compulsive Disorder, Pituitary-Adrenal System, DNA Methylation, Tacrolimus Binding Proteins, Epigenesis, Genetic, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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