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

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. SteinA. 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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.

Original language	English
Article number	1908
Number of pages	15
Journal	Nature Communications
Volume	16
Issue number	1
Early online date	24 Feb 2025
DOIs	https://doi.org/10.1038/s41467-024-55356-x
Publication status	E-pub ahead of print - 24 Feb 2025

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Davyson, E., Shen, X., Huider, F., Adams, M. J., Borges, K., McCartney, D. L., Barker, L. F., van Dongen, J., Boomsma, D. I., Weihs, A., Grabe, H. J., Kühn, L., Teumer, A., Völzke, H., Zhu, T., Kaprio, J., Ollikainen, M., David, F. S., Meinert, S., ... McIntosh, A. M. (2025). Insights from a methylome-wide association study of antidepressant exposure. Nature Communications, 16(1), Article 1908. Advance online publication. https://doi.org/10.1038/s41467-024-55356-x

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title = "Insights from a methylome-wide association study of antidepressant exposure",

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.",

author = "E. Davyson and X. Shen and F. Huider and Adams, {M. J.} and K. Borges and McCartney, {D. L.} and Barker, {L. F.} and {van Dongen}, J. and Boomsma, {D. I.} and A. Weihs and Grabe, {H. J.} and L. K{\"u}hn and A. Teumer and H. V{\"o}lzke and T. Zhu and J. Kaprio and M. Ollikainen and David, {F. S.} and S. Meinert and F. Stein and Forstner, {A. J.} and U. Dannlowski and T. Kircher and A. Tapuc and D. Czamara and Binder, {E. B.} and T. Br{\"u}ckl and Kwong, {A. S. F.} and P. Yousefi and Wong, {C. C. Y.} and L. Arseneault and Fisher, {H. L.} and J. Mill and Cox, {S. R.} and P. Redmond and Russ, {T. C.} and {van den Oord}, {E. J. C. G.} and Aberg, {K. A.} and Penninx, {B. W. J. H.} and Marioni, {R. E.} and Wray, {N. R.} and McIntosh, {A. M.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

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doi = "10.1038/s41467-024-55356-x",

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Davyson, E, Shen, X, Huider, F, Adams, MJ, Borges, K, McCartney, DL, Barker, LF, van Dongen, J, Boomsma, DI, Weihs, A, Grabe, HJ, 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, ASF , Yousefi, P, Wong, CCY, Arseneault, L, Fisher, HL, Mill, J, Cox, SR, Redmond, P, Russ, TC, van den Oord, EJCG, Aberg, KA, Penninx, BWJH, Marioni, RE, Wray, NR & McIntosh, AM 2025, 'Insights from a methylome-wide association study of antidepressant exposure', Nature Communications, vol. 16, no. 1, 1908. https://doi.org/10.1038/s41467-024-55356-x

TY - JOUR

T1 - Insights from a methylome-wide association study of antidepressant exposure

AU - Davyson, E.

AU - Shen, X.

AU - Huider, F.

AU - Adams, M. J.

AU - Borges, K.

AU - McCartney, D. L.

AU - Barker, L. F.

AU - van Dongen, J.

AU - Boomsma, D. I.

AU - Weihs, A.

AU - Grabe, H. J.

AU - Kühn, L.

AU - Teumer, A.

AU - Völzke, H.

AU - Zhu, T.

AU - Kaprio, J.

AU - Ollikainen, M.

AU - David, F. S.

AU - Meinert, S.

AU - Stein, F.

AU - Forstner, A. J.

AU - Dannlowski, U.

AU - Kircher, T.

AU - Tapuc, A.

AU - Czamara, D.

AU - Binder, E. B.

AU - Brückl, T.

AU - Kwong, A. S. F.

AU - Yousefi, P.

AU - Wong, C. C. Y.

AU - Arseneault, L.

AU - Fisher, H. L.

AU - Mill, J.

AU - Cox, S. R.

AU - Redmond, P.

AU - Russ, T. C.

AU - van den Oord, E. J. C. G.

AU - Aberg, K. A.

AU - Penninx, B. W. J. H.

AU - Marioni, R. E.

AU - Wray, N. R.

AU - McIntosh, A. M.

PY - 2025/2/24

Y1 - 2025/2/24

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-024-55356-x

DO - 10.1038/s41467-024-55356-x

M3 - Article (Academic Journal)

C2 - 39994233

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1908

ER -

Insights from a methylome-wide association study of antidepressant exposure

Abstract

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