Epigenetic markers of disease risk and psychotherapy response in anxiety disorders – a longitudinal analysis of the DNA methylome
Epigenetic mechanisms such as DNA methylation are hypothesized to play a pivotal role in the pathogenesis of anxiety disorders and to predict as well as relate to treatment response. An epigenome-wide association study (EWAS) (Illumina MethylationEPIC BeadChip) was performed at baseline (BL), post-treatment (POST) and 6-month follow-up (FU) in the so far largest longitudinal sample of patients with anxiety disorders (N = 415) treated with exposure-based cognitive behavioral therapy (CBT), and in 315 healthy controls. Independent of comorbidity with depression, anxiety disorders were significantly (p ≤ 6.409E-08) associated with altered DNA methylation at 148 CpGs partly mapping to genes previously implicated in processes related to anxiety, brain disorders, learning or plasticity (e.g., GABBR2, GABRD, GAST, IL12RB2, LINC00293, LOC101928626, MFGE8, NOTCH4, PTPRN2, RIMBP2, SPTBN1) or in a recent cross-anxiety disorders EWAS (TAOK1) after pre-processing and quality control (N = 378 vs. N = 295). Furthermore, BL DNA methylation at seven and three CpGs, respectively, was suggestively (p < 1E-5) associated with treatment response at POST (ABCA7, ADRA2C, LTBR, RPSAP52, SH3RF3, SLC47A2, ZNF251) and FU (ADGRD1, PRSS58, USP47). Finally, suggestive evidence for dynamic epigenome-wide DNA methylation changes along with CBT response emerged at four CpGs from BL to FU (ADIPOR2, EIF3B, OCA2, TMCC1). The identification of epigenetic biomarkers may eventually aid in developing environment-based preventive strategies aimed at increasing resilience by providing deeper molecular insights into the mechanisms underlying anxiety disorders. Defining epigenetic signatures as predictors or key mechanisms in exposure-based interventions could pave the way for more targeted and personalized treatments for anxiety disorders.
Authors
- Katharina Domschke (ORCID: https://orcid.org/0000-0002-2550-9132)
- Andre Pittig (ORCID: https://orcid.org/0000-0003-3787-9576)
- Paul Pauli (ORCID: https://orcid.org/0000-0003-0692-6720)
- Ingmar Heinig (ORCID: https://orcid.org/0000-0002-7762-4327)
- Ulrike Lueken (ORCID: https://orcid.org/0000-0003-1564-4012)
- Silvia Schneider (ORCID: https://orcid.org/0000-0003-0698-8411)
- Katja Koelkebeck (ORCID: https://orcid.org/0000-0002-0469-3997)
- Maike Hollandt (ORCID: https://orcid.org/0000-0001-5052-7271)
- Elisabeth B. Binder (ORCID: https://orcid.org/0000-0001-7088-6618)
- Miriam A. Schiele (ORCID: https://orcid.org/0000-0003-2613-6515)
- Jan Richter (ORCID: https://orcid.org/0000-0002-7127-6990)
- Isabelle C. Ridderbusch
- Alfons O. Hamm (ORCID: https://orcid.org/0000-0002-3352-6231)
- Jens Plag (ORCID: https://orcid.org/0000-0002-8838-2490)
- J. Deckert
- Thomas Fydrich (ORCID: https://orcid.org/0000-0003-0122-2302)
- Pascal Schlosser (ORCID: https://orcid.org/0000-0002-8460-0462)
- Jürgen Margraf (ORCID: https://orcid.org/0000-0001-5207-7016)
- Benjamin Straube (ORCID: https://orcid.org/0000-0002-9837-0944)
- Winfried Rief (ORCID: https://orcid.org/0000-0002-7019-2250)
- Angelika Erhardt (ORCID: https://orcid.org/0000-0002-2840-7633)
- Andreas Ströhle (ORCID: https://orcid.org/0000-0003-0935-3702)
- Udo Dannlowski (ORCID: https://orcid.org/0000-0002-0623-3759)
- Tilo T. J. Kircher (ORCID: https://orcid.org/0000-0002-2514-2625)
- Jan Lipovsek
- Anna Köttgen (ORCID: https://orcid.org/0000-0002-4671-3714)
- Lea Zillich (ORCID: https://orcid.org/0000-0001-7457-374X)
- Volker Arolt (ORCID: https://orcid.org/0000-0002-2445-9778)
- Hans‐Ulrich Wïttchen (ORCID: https://orcid.org/0000-0002-6311-7711)
- Jürgen Hoyer (ORCID: https://orcid.org/0000-0002-1697-6732)
- Óscar Crespo Salvador
- Heike Weber (ORCID: https://orcid.org/0000-0002-9421-1292)
Institutions
- Johns Hopkins University (US)
- University of Hildesheim (DE)
- University of Freiburg (DE)
- Philipps University of Marburg (DE)
- University of Würzburg (DE)
- Universitätsmedizin Greifswald (DE)
- University Medical Center Freiburg (DE)
- Humboldt-Universität zu Berlin (DE)
- Universitätsklinikum Würzburg (DE)
- German Centre for Cardiovascular Research (DE)
- Max Planck Institute of Psychiatry (DE)
- University of Duisburg-Essen (DE)
- University of Göttingen (DE)
- Technische Universität Dresden (DE)
- Charité - Universitätsmedizin Berlin (DE)
- Ruhr University Bochum (DE)
Publication Details
- Journal
- Molecular Psychiatry
- Published
- 2025-04-25
- DOI
- https://doi.org/10.1038/s41380-025-03038-5
- Citations
- 12
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 9.67
Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Max-Planck-Gesellschaft
- European College of Neuropsychopharmacology