Insights from a methylome-wide association study of antidepressant exposure

E Davyson; X Shen; F Huider; M J Adams; K Borges; D L McCartney; L F Barker; J van Dongen; D I Boomsma; A Weihs; H J Grabe; L Kühn; A Teumer; H Völzke; T Zhu; J Kaprio; M Ollikainen; F S David; S Meinert; F Stein; A J Forstner; U Dannlowski; T Kircher; A Tapuc; D Czamara; E B Binder; T Brückl; A S F Kwong; P Yousefi; C C Y Wong; L Arseneault; H L Fisher; J Mill; S R Cox; P Redmond; T C Russ; E J C G van den Oord; K A Aberg; B W J H Penninx; R E Marioni; N R Wray; A M McIntosh

doi:10.1038/s41467-024-55356-x

Insights from a methylome-wide association study of antidepressant exposure

Nat Commun. 2025 Feb 24;16(1):1908. doi: 10.1038/s41467-024-55356-x.

Authors

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.

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.

MeSH terms

Adult
Aged
Antidepressive Agents* / pharmacology
Antidepressive Agents* / therapeutic use
CpG Islands / genetics
DNA Methylation* / drug effects
Depression* / drug therapy
Depression* / genetics
Epigenome*
Female
Genome-Wide Association Study
Humans
Male
Middle Aged
Scotland
Self Report

Substances

Antidepressive Agents

Abstract

MeSH terms

Substances

Grants and funding