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. 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. Oord, K. A. Aberg, B. W. J. H. Penninx, R. E. Marioni, N. R. Wray and A. M. McIntosh ()
Additional contact information
E. Davyson: University of Edinburgh
X. Shen: University of Edinburgh
F. Huider: Vrije Universiteit Amsterdam
M. J. Adams: University of Edinburgh
K. Borges: University of Edinburgh
D. L. McCartney: University of Edinburgh
L. F. Barker: University of Queensland
J. Dongen: Vrije Universiteit Amsterdam
D. I. Boomsma: Vrije Universiteit Amsterdam
A. Weihs: University Medicine Greifswald
H. J. Grabe: University Medicine Greifswald
L. Kühn: University Medicine Greifswald
A. Teumer: University Medicine Greifswald
H. Völzke: Partner Site Greifswald
T. Zhu: University of Helsinki
J. Kaprio: University of Helsinki
M. Ollikainen: University of Helsinki
F. S. David: School of Medicine & University Hospital Bonn
S. Meinert: University of Münster
F. Stein: University of Marburg
A. J. Forstner: School of Medicine & University Hospital Bonn
U. Dannlowski: University of Münster
T. Kircher: University of Marburg
A. Tapuc: Max Planck School of Cognition
D. Czamara: Department Genes and Environment
E. B. Binder: Department Genes and Environment
T. Brückl: Department Genes and Environment
A. S. F. Kwong: University of Edinburgh
P. Yousefi: University of Bristol
C. C. Y. Wong: King’s College London
L. Arseneault: King’s College London
H. L. Fisher: King’s College London
J. Mill: University of Exeter
S. R. Cox: University of Edinburgh
P. Redmond: University of Edinburgh
T. C. Russ: University of Edinburgh
E. J. C. G. Oord: Virginia Commonwealth University
K. A. Aberg: Virginia Commonwealth University
B. W. J. H. Penninx: Vrije Universiteit Amsterdam
R. E. Marioni: University of Edinburgh
N. R. Wray: University of Queensland
A. M. McIntosh: University of Edinburgh

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55356-x

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