Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system
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Abstract
Abstract Antidepressants are an effective treatment for major depressive disorder (MDD), although individual response is unpredictable and highly variable. Whilst the mode of action of antidepressants is incompletely understood, many medications are associated with changes in DNA methylation in genes that are plausibly linked to their mechanisms. Studies of DNA methylation may therefore reveal the biological processes underpinning the efficacy and side effects of antidepressants. We performed a methylome-wide association study (MWAS) of self-reported antidepressant use accounting for lifestyle factors and MDD in Generation Scotland (GS:SFHS, N = 6428, EPIC array) and the Netherlands Twin Register (NTR, N = 2449, 450 K array) and ran a meta-analysis of antidepressant use across these two cohorts. We found ten CpG sites significantly associated with self-reported antidepressant use in GS:SFHS, with the top CpG located within a gene previously associated with mental health disorders, ATP6V1B2 ( β = −0.055, p corrected = 0.005). Other top loci were annotated to genes including CASP10, TMBIM1, MAPKAPK3 , and HEBP2 , which have previously been implicated in the innate immune response. Next, using penalised regression, we trained a methylation-based score of self-reported antidepressant use in a subset of 3799 GS:SFHS individuals that predicted antidepressant use in a second subset of GS:SFHS ( N = 3360, β = 0.377, p = 3.12 × 10 −11 , R 2 = 2.12%). In an MWAS analysis of prescribed selective serotonin reuptake inhibitors, we showed convergent findings with those based on self-report. In NTR, we did not find any CpGs significantly associated with antidepressant use. The meta-analysis identified the two CpGs of the ten above that were common to the two arrays used as being significantly associated with antidepressant use, although the effect was in the opposite direction for one of them. Antidepressants were associated with epigenetic alterations in loci previously associated with mental health disorders and the innate immune system. These changes predicted self-reported antidepressant use in a subset of GS:SFHS and identified processes that may be relevant to our mechanistic understanding of clinically relevant antidepressant drug actions and side effects.
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Cross-referencing of presently identified hits with the 10 CpGs reported to be associated with antidepressant use in a recent EWAS did not reveal any overlap.
“However, cross-referencing of the presently identified hits suggestively predicting antidepressant treatment response with the 10 CpGs reported to be associated with antidepressant use in a recent EWAS (Barbu et al., 2022) did not reveal any overlap.”
From Epigenome-wide DNA methylation in unipolar depression: predictive biomarker of antidepressant treatment response? (2024) · cites this paper as Barbu et al., 2022
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Self-citation
Flagged first, then by citations
Research works printed but not linked: 2
- [57]Liu C Marioni RE Hedman AK Pfeiffer L Tsai PC Reynolds LM A DNA methylation biomarker of alcohol consumption Mol Psychiatry 2018 23 422 33 10.1038/mp.2016.192 27843151 PMC5575985 · DOI · Paper page
- [58]Joehanes R Just AC Marioni RE Pilling LC Reynolds LM Mandaviya PR Epigenetic signatures of cigarette smoking Circ Cardiovasc Genet 2016 9 436 47 10.1161/CIRCGENETICS.116.001506 27651444 PMC5267325 · DOI
Cited by
Sorted by citations
Engelmann, J., Zillich, L., Frank, J., Wagner, S., Cetin, M., Herzog, D. P., Müller, M. B., Tadic, A., Foo, J. C., Sirignano, L., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02032-7 · Cited by 29 · see citing works
Schiele, M. A., Crespo Salvador, O., Lipovsek, J., Schwarte, K., Schlosser, P., Zwanzger, P., Arolt, V., Baune, B. T., Köttgen, A., & Domschke, K. (2024) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyae045 · Cited by 13 · see citing works
- Authors
- Barbu, M. C., Huider, F., Campbell, A., Amador, C., Adams, M. J., Lynall, M.-E., Howard, D. M., Walker, R. M., Morris, S. W., Van Dongen, J., Porteous, D. J., Evans, K. L., Bullmore, E., Willemsen, G., Boomsma, D. I., Whalley, H. C., & McIntosh, A. M.
- Affiliations
- Royal Edinburgh Hospital (GB)
- Vrije Universiteit Amsterdam (NL)
- Institute of Genetics and Cancer (GB)
- University of Cambridge (GB)
- King's College London (GB)
- Corresponding author
- Barbu, Miruna C.
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2021-12-08
- Volume
- 27
- Issue
- 3
- Pages
- 1647-1657
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC9095457
- OpenAlex
- W4200085093
- Cited by
- 43
- References
- 82
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 21 · 2021: 1
- FWCI
- 2.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Molecular Psychiatry (publishedVersion, cc-by)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Apollo (cc-by)
- Funders
- National Alliance for Research on Schizophrenia and Depression (27404)
- Wellcome Trust (220857/Z/20/Z, 220857, 213674/Z/18/Z, 104036/Z/14/Z, 104036, 213674)
- Scottish Government (CZD/16/6)
- Royal College of Physicians of Edinburgh
- National Institute for Health and Care Research (NF-SI-0513-10051, NIHR200256)
- Scottish Funding Council (HR03006)
- Guarantors of Brain
- Chief Scientist Office, Scottish Government Health and Social Care Directorate (HR03006, CZD/16/6)
- Medical Research Council (104036/Z/14/Z, MC_G0802534, MR/W014386/1, MC_UU_00007/10, MR/S006257/1)
- Topics
- 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
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- antidepressant use, DNA methylation, methylome-wide association study, innate immune system, major depressive disorder, selective serotonin reuptake inhibitors, ATP6V1B2, caspase-10, MAPKAPK3, epigenetic biomarkers, antidepressant side effects, Generation Scotland, Netherlands Twin Register
- MeSH terms
- Heme-Binding Proteins, Epigenome, Antidepressive Agents, Major Depressive Disorder, Humans, Immune System, Netherlands, Pregnancy Proteins, Scotland
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.
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