Insights from a methylome-wide association study of antidepressant exposure

E Davyson^{1

2}, X Shen¹, F Huider^{3

4

5}, M J Adams¹, K Borges¹, D L McCartney², L F Barker⁶, J van Dongen^{3

4

5

7}, D I Boomsma^{3

4

7}, A Weihs^{8

9}, H J Grabe^{8

9}, L Kühn⁸, A Teumer^{8

10}, H Völzke^{10

11}, T Zhu^{12

13}, J Kaprio¹², M Ollikainen^{12

13}, F S David^{14

15}, S Meinert^{16

17}, F Stein^{15

18}, A J Forstner^{14

19

20}, U Dannlowski¹⁶, T Kircher^{15

18}, A Tapuc^{21

22}, D Czamara²², E B Binder²², T Brückl²², A S F Kwong^{1

23}, P Yousefi^{23

24

25}, C C Y Wong²⁶, L Arseneault²⁶, H L Fisher^{26

27}, J Mill²⁸, S R Cox²⁹, P Redmond²⁹, T C Russ^{1

30

31}, E J C G van den Oord³², K A Aberg³², B W J H Penninx³³, R E Marioni², N R Wray^{6

34}, A M McIntosh³⁵

Affiliations

¹ Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
² Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
³ Complex Trait Genetics, Center of Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁴ Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
⁵ Department of Biological Psychiatry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁶ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.
⁷ Amsterdam Reproduction & Development, Research Institute, Amsterdam, The Netherlands.
⁸ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475, Greifswald, Germany.
⁹ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, 17489, Greifswald, Germany.
¹⁰ German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, 17489, Greifswald, Germany.
¹¹ Department SHIP/Clinical-Epidemiological Research, Institute for Community Medicine, University Medicine Greifswald, 17475, Greifswald, Germany.
¹² Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
¹³ Minerva Foundation Institute for Medical Research, Helsinki, Finland.
¹⁴ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
¹⁵ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
¹⁶ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
¹⁷ Institute for Translational Neuroscience, University of Münster, Münster, Germany.
¹⁸ Center for Mind, Brain and Behavior, University of Marburg, Marburg, Germany.
¹⁹ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
²⁰ Center for Human Genetics, University of Marburg, Marburg, Germany.
²¹ Max Planck School of Cognition, Leipzig, Germany.
²² Max-Planck-Institute of Psychiatry, Department Genes and Environment, Munich, Germany.
²³ Medical Research Council Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Bristol, UK.
²⁴ Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.
²⁵ NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and University of Bristol, Bristol, UK.
²⁶ Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
²⁷ ESRC Centre for Society and Mental Health, King's College London, London, UK.
²⁸ Department of Clinical & Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.
²⁹ Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK.
³⁰ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
³¹ Neuroprogressive and Dementia Network, NHS Research Scotland, Scotland, UK.
³² Center for Biomarker Research and Precision Medicine (BPM), Virginia Commonwealth University, Virginia, USA.
³³ Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
³⁴ Department of Psychiatry, University of Oxford, Oxford, UK.
³⁵ Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. andrew.mcintosh@ed.ac.uk.

PMID: 39994233
PMCID: PMC11850842
DOI: 10.1038/s41467-024-55356-x

Insights from a methylome-wide association study of antidepressant exposure

E Davyson et al. Nat Commun. 2025.

. 2025 Feb 24;16(1):1908.

doi: 10.1038/s41467-024-55356-x.

Authors

Affiliations

¹ Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
² Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
³ Complex Trait Genetics, Center of Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁴ Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
⁵ Department of Biological Psychiatry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁶ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.
⁷ Amsterdam Reproduction & Development, Research Institute, Amsterdam, The Netherlands.
⁸ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475, Greifswald, Germany.
⁹ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, 17489, Greifswald, Germany.
¹⁰ German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, 17489, Greifswald, Germany.
¹¹ Department SHIP/Clinical-Epidemiological Research, Institute for Community Medicine, University Medicine Greifswald, 17475, Greifswald, Germany.
¹² Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
¹³ Minerva Foundation Institute for Medical Research, Helsinki, Finland.
¹⁴ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
¹⁵ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
¹⁶ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
¹⁷ Institute for Translational Neuroscience, University of Münster, Münster, Germany.
¹⁸ Center for Mind, Brain and Behavior, University of Marburg, Marburg, Germany.
¹⁹ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
²⁰ Center for Human Genetics, University of Marburg, Marburg, Germany.
²¹ Max Planck School of Cognition, Leipzig, Germany.
²² Max-Planck-Institute of Psychiatry, Department Genes and Environment, Munich, Germany.
²³ Medical Research Council Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Bristol, UK.
²⁴ Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.
²⁵ NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and University of Bristol, Bristol, UK.
²⁶ Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
²⁷ ESRC Centre for Society and Mental Health, King's College London, London, UK.
²⁸ Department of Clinical & Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.
²⁹ Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK.
³⁰ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
³¹ Neuroprogressive and Dementia Network, NHS Research Scotland, Scotland, UK.
³² Center for Biomarker Research and Precision Medicine (BPM), Virginia Commonwealth University, Virginia, USA.
³³ Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
³⁴ Department of Psychiatry, University of Oxford, Oxford, UK.
³⁵ Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. andrew.mcintosh@ed.ac.uk.

PMID: 39994233
PMCID: PMC11850842
DOI: 10.1038/s41467-024-55356-x

Abstract

This study tests the association of whole-blood DNA methylation and antidepressant exposure in 16,531 individuals from Generation Scotland (GS), using self-report and prescription-derived measures. We identify 8 associations and a high concordance of results between self-report and prescription-derived measures. Sex-stratified analyses observe nominally significant increased effect estimates in females for four CpGs. There is observed enrichment for genes expressed in the Amygdala and annotated to synaptic vesicle membrane ontology. Two CpGs (cg15071067; DGUOK-AS1 and cg26277237; KANK1) show correlation between DNA methylation with the time in treatment. There is a significant overlap in the top 1% of CpGs with another independent methylome-wide association study of antidepressant exposure. Finally, a methylation profile score trained on this sample shows a significant association with antidepressant exposure in a meta-analysis of eight independent external datasets. In this large investigation of antidepressant exposure and DNA methylation, we demonstrate robust associations which warrant further investigation to inform on the design of more effective and tolerated treatments for depression.

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Conflict of interest statement

Competing interests: R.E.M. is an advisor to the Epigenetic Clock Development Foundation and Optima Partners. D.L.M. was employed by Optima Partners Ltd in a part-time capacity. H.J.G. has received travel grants and speaker honoraria from Fresenius Medical Care, Neuraxpharm, Servier, Indorsia and Janssen Cilag, as well as research funding from Fresenius Medical Care. H.J.G. had personal contracts approved by the university administration for speaker honoraria and one IIT with Fresenius Medical Care. T.K. received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, neuraxpharm. B.W.J.H.P. has received research funding (not related to the current paper) from Boehringer Ingelheim and Jansen Research. All other authors report no biomedical financial interests or potential conflicts of interest.

Figures

**Fig. 1. Study design of investigating antidepressant exposure and DNA methylation.**
Data: Participants in Generation Scotland (GS) provided blood samples from which DNA methylation was measured. Their antidepressant exposure status was measured using both self-report questionnaires and prescription-derived measures. Prescription-derived measures: Repeated regular prescriptions over time (X axis) for antidepressants (purple bars) are merged to form active antidepressant treatment periods (blue bars). Individuals in an active treatment period at the time of blood sample (black cross) are classed as antidepressant exposed. Methylome-wide association studies: A methylome-wide association study (MWAS), subsequent regional analysis and functional annotation was performed for both measures of antidepressant exposure. Additionally, an enrichment analysis was done using MBD-Sequencing data in the Netherlands Depression and Anxiety (NESDA) cohort for the self-report antidepressant exposure. Methylation Profile Score: Weights for a methylation profile score (MPS) of self-reported antidepressant exposure was calculated in GS using a least absolute shrinkage and selection operator (LASSO) model. Eight independent datasets then tested the association of this MPS with self-reported antidepressant exposure. Created in BioRender. Davyson, E. (2024) https://BioRender.com/s43g100.

**Fig. 2. Methylome-wide association studies (MWAS) of self-reported and prescription-derived antidepressant exposure.**
Manhattan plots of the MWAS of self-report (A) and prescription-derived (B) antidepressant exposure using a Mixed-linear-model Omics-based Analysis (MOA) model. Significance was assessed using the p-value threshold 9.42 × 10⁻⁸, as recommended for case-control MWAS analyses. C The MOA MWAS standardised effect sizes and 95% confidence-intervals (effect estimate +/- 1.96*Standard Error) for associated CpGs (p < 9.42 × 10⁻⁸) for the full sample (N_self-report = 16,531, N_{prescription-derived} = 7951) and MDD-subgroup sample (N_self-report = 2268, N_{prescription-derived} = 792). Data are presented as the MWAS effect estimates +/- the 95% confidence intervals. Effect sizes represent a per-1 standard-deviation increase in CpG methylation M-values.

**Fig. 3. An antidepressant exposure methylation profile score (MPS) and antidepressant exposure in external cohorts.**
A The number of participants exposed and unexposed to antidepressants in each cohort (N_NTR = 3087, N_STRADL = 658, N_FTC = 1678, N_SHIP-TREND = 495, N_ALSPAC = 801, N_LBC1936 = 889, N_MARS-UniDep = 312, N_ERISK = 1658, N_FOR2107 = 658). B Nagelkerke’s pseudo R², representing an estimate of how much variance in the antidepressant exposure outcome that is explained by the MPS in each cohort. C The effect estimates and 95% confidence intervals (effect estimate +/− 1.96*Standard Error) of MPS ~ antidepressant exposure association in each cohort, using either a generalised linear model (FOR2107 and ALSPAC), a generalised linear mixed model (SHIP-Trend, LBC1936, MARS-UniDep, STRADL and E-Risk) or a generalised estimation equation model (FTC and NTR). The square size = study weight in the random-effects meta-analysis. The pooled effect estimate interval, calculated from a random-effects meta-analysis, is represented by the blue diamond (N_pooled=10,236). Created in BioRender. Davyson, E. (2024) https://BioRender.com/q70l792.

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Update of

Antidepressant Exposure and DNA Methylation: Insights from a Methylome-Wide Association Study.
Davyson E, Shen X, Huider F, Adams M, Borges K, McCartney D, Barker L, Van Dongen J, Boomsma D, Weihs A, Grabe H, Kühn L, Teumer A, Völzke H, Zhu T, Kaprio J, Ollikainen M, David FS, Meinert S, Stein F, Forstner AJ, Dannlowski U, Kircher T, Tapuc A, Czamara D, Binder EB, Brückl T, Kwong A, Yousefi P, Wong C, Arseneault L, Fisher HL, Mill J, Cox S, Redmond P, Russ TC, van den Oord E, Aberg KA, Penninx B, Marioni RE, Wray NR, McIntosh AM. Davyson E, et al. medRxiv [Preprint]. 2024 May 3:2024.05.01.24306640. doi: 10.1101/2024.05.01.24306640. medRxiv. 2024. Update in: Nat Commun. 2025 Feb 24;16(1):1908. doi: 10.1038/s41467-024-55356-x. PMID: 38746357 Free PMC article. Updated. Preprint.

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Insights from a methylome-wide association study of antidepressant exposure

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Insights from a methylome-wide association study of antidepressant exposure

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