Hpa axis related genes and response to psychological therapies: Genetics and epigenetics
Open accessAbstract
BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis functioning has been implicated in the development of stress-related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT). METHODS: Children with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response). RESULTS: Treatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response. CONCLUSIONS: Allele-specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner.
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Enhanced treatment response has also been associated with nominal increases in FKBP5 exon 1 methylation changes from pre- to post-CBT at one CpG site in 98 children and adolescents with mixed anxiety disorders, but again only in FKBP5 rs1360780 A risk allele carriers.
“Enhanced treatment response has also been associated with nominal increases in FKBP5 exon 1 methylation changes from preto post-CBT at one CpG site in 98 children and adolescents with mixed anxiety disorders, but again only in FKBP5 rs1360780 A risk allele carriers (Roberts et al., 2015).”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Roberts et al., 2015
The Results (DNA Methylation and Response to Therapy; page unavailable) report the opposite direction: increased FKBP5 methylation was associated with a smaller reduction in anxiety severity, while decreased methylation was associated with a greater reduction. The Discussion (page unavailable) reiterates that greater response was associated with decreases in methylation, including the same pattern among risk-genotype participants. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredDecreased FKBP5 methylation detected in saliva samples was associated with better CBT outcomes in a cohort of children diagnosed with anxiety between the ages of 8-15 years.
“Similar findings, with decreased FKBP5 methylation detected in saliva samples associated with better CBT outcomes, were also reported in a cohort of children diagnosed with anxiety between the ages of 8–15 years (Roberts et al., 2015).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Roberts et al., 2015
The Results (DNA Methylation and Response to Therapy; page unavailable) associate decreased FKBP5 methylation at CpG 4 with a greater reduction in anxiety severity after CBT, but the association did not survive correction for multiple testing. The Methods (DNA Methylation; page unavailable) explicitly say all methylation samples came from buccal swabs, not saliva. The copy identifies the participants as children with anxiety disorders but does not establish the stated 8–15-year age range. (LLM, conf=0.91)
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Patho- und Therapieepigenetik psychischer Erkrankungen
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Evaluation of Stress Management and Stress Prevention Using Epigenetic Markers
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Evaluation von Stressprävention und Stressbewältigung mittels epigenetischer Marker
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Bound Together: How Psychoanalysis Diminishes Inter-generational DNA Trauma
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Can Epigenetics Predict Drug Efficiency in Mental Disorders?
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Epigenetic Studies in Psychotherapy: A Systematic Review
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Epigenetic and Mental Diseases: The Role of Psychotherapy
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- Authors
- Roberts, S., Keers, R., Lester, K. J., Coleman, J. R. I., Breen, G., Arendt, K., Blatter‐Meunier, J., Cooper, P., Creswell, C., Fjermestad, K., Havik, O. E., Herren, C., Hogendoorn, S. M., Hudson, J. L., Krause, K., Lyneham, H. J., Morris, T., Nauta, M., Rapee, R. M., Rey, Y., Schneider, S., Schneider, S. C., Silverman, W. K., Thastum, M., Thirlwall, K., Waite, P., Eley, T. C., & Wong, C. C. Y.
- Affiliations
- King's College London (GB)
- University of Sussex (GB)
- National Health Service (GB)
- Aarhus University (DK)
- University of Basel (CH)
- Stellenbosch University (ZA)
- University of Reading (GB)
- Haukeland University Hospital (NO)
- De Bascule (NL)
- Macquarie University (AU)
- Ruhr University Bochum (DE)
- University of Groningen (NL)
- Florida International University (US)
- Yale University (US)
- Department of Psychology and Behavioural Sciences Aarhus University Aarhus Denmark
- Corresponding author
- Eley, Thalia C.
- Wong, Chloe C. Y.
- ORCID
- Roberts, Susanna
- Keers, Robert
- Lester, Kathryn J
- Coleman, Jonathan R. I.
- Breen, Gerome
- Arendt, Kristian
- Cooper, Peter
- Creswell, Cathy
- Fjermestad, Krister
- Hudson, Jennifer L.
- Krause, Karen
- Morris, Talia
- Nauta, Maaike
- Rapee, Ronald M.
- Rey, Yasmin
- Schneider, Silvia
- Schneider, Sophie C.
- Silverman, Wendy K.
- Waite, Polly
- Eley, Thalia C.
- Wong, Chloe C. Y.
- Venue
- Depression and Anxiety
- Publisher
- Hindawi Limited
- Published
- 2015-10-07
- Volume
- 32
- Issue
- 12
- Pages
- 861-870
- ISSN
- 1091-4269 (ISSN-L)
- 1520-6394
- PMC
- PMC4982063
- OpenAlex
- W1913150253
- Cited by
- 107
- References
- 43
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 6 · 2023: 7 · 2022: 8 · 2021: 7 · 2020: 14 · 2019: 8 · 2018: 31 · 2017: 9 · 2016: 7 · 2014: 1
- FWCI
- 8.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Depression and Anxiety (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CentAUR (University of Reading) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Sussex Research Online (University of Sussex) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion, cc-by)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
- Funders
- National Science Foundation
- Eli Lilly and Company
- South London and Maudsley NHS Foundation Trust
- National Institute for Health and Care Research (RP_2014-04-018, PB-PG-0110-21190, PB‐PG‐0107‐12042)
- King's College London
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (116517)
- Jacobs Foundation
- TrygFonden
- Medical Research Council (G1002011, 488505, G0901874/1, G0901874, MR/J011762/1, 382008, MR/K021281/1, G0601874, G0802326, 1027556)
- Australian Research Council (DP0878609)
- National Health and Medical Research Council (1027556, 488505, 382008)
- National Institute of Mental Health (R01MH079943, MH079943)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Keywords
- hypothalamic-pituitary-adrenal axis, FKBP5, glucocorticoid receptor, DNA methylation, epigenetics, cognitive behavioral therapy, treatment response, childhood anxiety disorders, genetic polymorphism, stress-related psychiatric disorders, allele-specific methylation
- MeSH terms
- Tacrolimus Binding Protein 5, Adolescent, Alleles, Anxiety Disorders, Child, Child, Preschool, Female, Humans, Hypothalamo-Hypophyseal System, Male, Pituitary-Adrenal System, Receptors, Glucocorticoid, Cognitive Behavioral Therapy, Treatment Outcome, DNA Methylation, Polymorphism, Single Nucleotide, Tacrolimus Binding Proteins, Epigenesis, Genetic, Epigenomics
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