Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system

Miruna C Barbu; Floris Huider; Archie Campbell; Carmen Amador; Mark J Adams; Mary-Ellen Lynall; David M Howard; Rosie M Walker; Stewart W Morris; Jenny van Dongen; David J Porteous; Kathryn L Evans; Edward Bullmore; Gonneke Willemsen; Dorret I Boomsma; Heather C Whalley; Andrew M McIntosh

doi:10.1038/s41380-021-01412-7

Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system

Miruna C Barbu, Floris Huider, Archie Campbell, Carmen Amador, Mark J Adams, Mary-Ellen Lynall, David M Howard, Rosie M Walker, Stewart W Morris, Jenny van Dongen, David J Porteous, Kathryn L Evans, Edward Bullmore, Gonneke Willemsen, Dorret I Boomsma, Heather C Whalley, Andrew M McIntosh

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

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, pcorrected = 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, R2 = 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.

Original language	English
Pages (from-to)	1647-1657
Number of pages	11
Journal	Molecular Psychiatry
Volume	27
Issue number	3
Early online date	8 Dec 2021
DOIs	https://doi.org/10.1038/s41380-021-01412-7
Publication status	Published - Mar 2022

Bibliographical note

Funding

EB is an NIHR Senior Investigator and is a member of the scientific advisory board of Sosei Heptares. ML is supported by a fellowship from the Medical Research Council (MR/S006257/1). Generation Scotland is currently supported by the Wellcome Trust Investigator Award in Science 01/06/2021 to 31/05/26 ‘Exploiting genomic approaches to identify the environmental basis of depression’. (Reference: 220857/Z/20/Z) to AMM. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The DNA methylation profiling and data preparation was supported by Wellcome Investigator Award 220857/Z/20/Z and Grant 104036/Z/14/Z (PI for both grants: AMM) and through funding from NARSAD (Ref: 27404; PI: DMH and Ref: 21956; PI: KLE) and the Royal College of Physicians of Edinburgh (Sim Fellowship; PI: HCW). CA was supported by an MRC University Unit award to the MRC Human Genetics Unit, University of Edinburgh, MC_UU_00007/10. Genotyping of the GS:SFHS samples was funded by the MRC and Wellcome Trust [104036/Z/14/Z]. Generation Scotland also receives support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. DMH is supported by a Sir Henry Wellcome Postdoctoral Fellowship (Reference 213674/Z/18/Z). MCB is supported by a Guarantors of Brain Non-clinical Post-Doctoral Fellowship. EB is an NIHR Senior Investigator and is a member of the scientific advisory board of Sosei Heptares. ML is supported by a fellowship from the Medical Research Council (MR/S006257/1). AMM has previously received grant support from Pfizer, Lilly and Janssen. These studies are not connected to the current investigation. Remaining authors report no conflicts of interest.

Funders	Funder number
Sir Henry Wellcome Postdoctoral Fellowship
University of Edinburgh
Royal College of Physicians of Edinburgh
National Institute for Health and Care Research
Pfizer
Lilly and Janssen
Scottish Funding Council	213674/Z/18/ Z, HR03006
Wellcome Trust	104036/Z/14/Z, 220857, 104036, 01/06/2021, 220857/Z/20/Z
Chief Scientist Office of the Scottish Government Health Directorates	CZD/16/6
UK Research and Innovation	MC_UU_00007/10
Medical Research Council	MR/S006257/1
National Alliance for Research on Schizophrenia and Depression	27404, 21956

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41380-021-01412-7

Persistent URL (handle)

Persistent link

Cite this

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. (2022). Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system. Molecular Psychiatry, 27(3), 1647-1657. https://doi.org/10.1038/s41380-021-01412-7

@article{6cd4acfd200e46efb24d45c6a14f2de3,

title = "Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system",

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, pcorrected = 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, R2 = 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.",

author = "Barbu, \{Miruna C\} and Floris Huider and Archie Campbell and Carmen Amador and Adams, \{Mark J\} and Mary-Ellen Lynall and Howard, \{David M\} and Walker, \{Rosie M\} and Morris, \{Stewart W\} and \{van Dongen\}, Jenny and Porteous, \{David J\} and Evans, \{Kathryn L\} and Edward Bullmore and Gonneke Willemsen and Boomsma, \{Dorret I\} and Whalley, \{Heather C\} and McIntosh, \{Andrew M\}",

note = "{\textcopyright} 2021. The Author(s).",

year = "2022",

month = mar,

doi = "10.1038/s41380-021-01412-7",

language = "English",

volume = "27",

pages = "1647--1657",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature",

number = "3",

}

Barbu, MC, Huider, F, Campbell, A, Amador, C, Adams, MJ, Lynall, M-E, Howard, DM, Walker, RM, Morris, SW, van Dongen, J, Porteous, DJ, Evans, KL, Bullmore, E, Willemsen, G, Boomsma, DI, Whalley, HC & McIntosh, AM 2022, 'Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system', Molecular Psychiatry, vol. 27, no. 3, pp. 1647-1657. https://doi.org/10.1038/s41380-021-01412-7

TY - JOUR

T1 - Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system

AU - Barbu, Miruna C

AU - Huider, Floris

AU - Campbell, Archie

AU - Amador, Carmen

AU - Adams, Mark J

AU - Lynall, Mary-Ellen

AU - Howard, David M

AU - Walker, Rosie M

AU - Morris, Stewart W

AU - van Dongen, Jenny

AU - Porteous, David J

AU - Evans, Kathryn L

AU - Bullmore, Edward

AU - Willemsen, Gonneke

AU - Boomsma, Dorret I

AU - Whalley, Heather C

AU - McIntosh, Andrew M

PY - 2022/3

Y1 - 2022/3

N2 - 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, pcorrected = 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, R2 = 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.

AB - 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, pcorrected = 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, R2 = 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.

UR - https://www.scopus.com/pages/publications/85120796030

UR - https://www.scopus.com/inward/citedby.url?scp=85120796030&partnerID=8YFLogxK

U2 - 10.1038/s41380-021-01412-7

DO - 10.1038/s41380-021-01412-7

M3 - Article

C2 - 34880450

SN - 1359-4184

VL - 27

SP - 1647

EP - 1657

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 3

ER -

Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system

Abstract

Bibliographical note

Funding

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this