Genome-wide association study of antidepressant treatment resistance in a population-based cohort using health service prescription data and meta-analysis with GENDEP

Eleanor M. Wigmore; Jonathan D. Hafferty; Lynsey S. Hall; David M. Howard; Toni Kim Clarke; Chiara Fabbri; Cathryn M. Lewis; Rudolf Uher; Lauren B. Navrady; Mark J. Adams; Yanni Zeng; Archie Campbell; Jude Gibson; Pippa A. Thomson; Caroline Hayward; Blair H. Smith; Lynne J. Hocking; Sandosh Padmanabhan; Ian J. Deary; David J. Porteous; Ole Mors; Manuel Mattheisen; Kristin K. Nicodemus; Andrew M. McIntosh

doi:10.1038/s41397-019-0067-3

Genome-wide association study of antidepressant treatment resistance in a population-based cohort using health service prescription data and meta-analysis with GENDEP

Eleanor M. Wigmore, Jonathan D. Hafferty, Lynsey S. Hall, David M. Howard, Toni Kim Clarke, Chiara Fabbri, Cathryn M. Lewis, Rudolf Uher, Lauren B. Navrady, Mark J. Adams, Yanni Zeng, Archie Campbell, Jude Gibson, Pippa A. Thomson, Caroline Hayward, Blair H. Smith, Lynne J. Hocking, Sandosh Padmanabhan, Ian J. Deary, David J. PorteousOle Mors, Manuel Mattheisen, Kristin K. Nicodemus, Andrew M. McIntosh

Medicine

Research output: Contribution to journal › Article › peer-review

55 Citations (Scopus)

Abstract

Antidepressants demonstrate modest response rates in the treatment ofmajor depressive disorder (MDD). Despite previous genome-wide association studies(GWAS) of antidepressant treatment response, the underlying genetic factors areunknown. Using prescription data in a population and family-based cohort (GenerationScotland: Scottish Family Health Study; GS:SFHS), we sought to define a measure of(a) antidepressant treatment resistance and (b) stages of antidepressant resistanceby inferring antidepressant switching as non-response to treatment. GWAS wereconducted separately for antidepressant treatment resistance in GS:SFHS and theGenome-based Therapeutic Drugs for Depression (GENDEP) study and then meta-analysed(meta-analysis n = 4213, cases = 358). For stagesof antidepressant resistance, a GWAS on GS:SFHS only was performed (n = 3452). Additionally, we conducted gene-setenrichment, polygenic risk scoring (PRS) and genetic correlation analysis. We didnot identify any significant loci, genes or gene sets associated with antidepressanttreatment resistance or stages of resistance. Significant positive geneticcorrelations of antidepressant treatment resistance and stages of resistance withneuroticism, psychological distress, schizotypy and mood disorder traits wereidentified. These findings suggest that larger sample sizes are needed to identifythe genetic architecture of antidepressant treatment response, and thatpopulation-based observational studies may provide a tractable approach to achievingthe necessary statistical power.

Original language	English
Pages (from-to)	329-341
Number of pages	13
Journal	Pharmacogenomics Journal
Volume	20
Issue number	2
DOIs	https://doi.org/10.1038/s41397-019-0067-3
Publication status	Published - Apr 1 2020

Bibliographical note

Funding Information:
Acknowledgements This investigation was supported by the Wellcome Trust 104036/Z/14/Z (STRADL, Stratifying Resilience and Depression Longitudinally). Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6 and the Scottish Funding Council HR03006. We thank all families, practitioners and the Scottish School of Primary Care involved in the recruitment process as well as the entirety of Generation Scotland team; interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. We are grateful to the Sackler Foundation for the generous support of this work. IJD is supported by MRC and BBSRC funding to the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (MR/ K026992/1).

Funding Information:
Conflict of interest AMM has received financial support from Pfizer (formerly Wyeth), Janssen and Lilly and from the Sackler trust. The remaining authors declare that they have no conflict of interest.

Publisher Copyright:
© 2019, The Author(s).

ASJC Scopus Subject Areas

Molecular Medicine
Genetics
Pharmacology

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10.1038/s41397-019-0067-3

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Wigmore, E. M., Hafferty, J. D., Hall, L. S., Howard, D. M., Clarke, T. K., Fabbri, C., Lewis, C. M., Uher, R., Navrady, L. B., Adams, M. J., Zeng, Y., Campbell, A., Gibson, J., Thomson, P. A., Hayward, C., Smith, B. H., Hocking, L. J., Padmanabhan, S., Deary, I. J., ... McIntosh, A. M. (2020). Genome-wide association study of antidepressant treatment resistance in a population-based cohort using health service prescription data and meta-analysis with GENDEP. Pharmacogenomics Journal, 20(2), 329-341. https://doi.org/10.1038/s41397-019-0067-3

Genome-wide association study of antidepressant treatment resistance in a population-based cohort using health service prescription data and meta-analysis with GENDEP. / Wigmore, Eleanor M.; Hafferty, Jonathan D.; Hall, Lynsey S. et al.
In: Pharmacogenomics Journal, Vol. 20, No. 2, 01.04.2020, p. 329-341.

Research output: Contribution to journal › Article › peer-review

Wigmore, EM, Hafferty, JD, Hall, LS, Howard, DM, Clarke, TK, Fabbri, C, Lewis, CM, Uher, R, Navrady, LB, Adams, MJ, Zeng, Y, Campbell, A, Gibson, J, Thomson, PA, Hayward, C, Smith, BH, Hocking, LJ, Padmanabhan, S, Deary, IJ, Porteous, DJ, Mors, O, Mattheisen, M, Nicodemus, KK & McIntosh, AM 2020, 'Genome-wide association study of antidepressant treatment resistance in a population-based cohort using health service prescription data and meta-analysis with GENDEP', Pharmacogenomics Journal, vol. 20, no. 2, pp. 329-341. https://doi.org/10.1038/s41397-019-0067-3

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abstract = "Antidepressants demonstrate modest response rates in the treatment ofmajor depressive disorder (MDD). Despite previous genome-wide association studies(GWAS) of antidepressant treatment response, the underlying genetic factors areunknown. Using prescription data in a population and family-based cohort (GenerationScotland: Scottish Family Health Study; GS:SFHS), we sought to define a measure of(a) antidepressant treatment resistance and (b) stages of antidepressant resistanceby inferring antidepressant switching as non-response to treatment. GWAS wereconducted separately for antidepressant treatment resistance in GS:SFHS and theGenome-based Therapeutic Drugs for Depression (GENDEP) study and then meta-analysed(meta-analysis n = 4213, cases = 358). For stagesof antidepressant resistance, a GWAS on GS:SFHS only was performed (n = 3452). Additionally, we conducted gene-setenrichment, polygenic risk scoring (PRS) and genetic correlation analysis. We didnot identify any significant loci, genes or gene sets associated with antidepressanttreatment resistance or stages of resistance. Significant positive geneticcorrelations of antidepressant treatment resistance and stages of resistance withneuroticism, psychological distress, schizotypy and mood disorder traits wereidentified. These findings suggest that larger sample sizes are needed to identifythe genetic architecture of antidepressant treatment response, and thatpopulation-based observational studies may provide a tractable approach to achievingthe necessary statistical power.",

author = "Wigmore, {Eleanor M.} and Hafferty, {Jonathan D.} and Hall, {Lynsey S.} and Howard, {David M.} and Clarke, {Toni Kim} and Chiara Fabbri and Lewis, {Cathryn M.} and Rudolf Uher and Navrady, {Lauren B.} and Adams, {Mark J.} and Yanni Zeng and Archie Campbell and Jude Gibson and Thomson, {Pippa A.} and Caroline Hayward and Smith, {Blair H.} and Hocking, {Lynne J.} and Sandosh Padmanabhan and Deary, {Ian J.} and Porteous, {David J.} and Ole Mors and Manuel Mattheisen and Nicodemus, {Kristin K.} and McIntosh, {Andrew M.}",

note = "Funding Information: Acknowledgements This investigation was supported by the Wellcome Trust 104036/Z/14/Z (STRADL, Stratifying Resilience and Depression Longitudinally). Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6 and the Scottish Funding Council HR03006. We thank all families, practitioners and the Scottish School of Primary Care involved in the recruitment process as well as the entirety of Generation Scotland team; interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. We are grateful to the Sackler Foundation for the generous support of this work. IJD is supported by MRC and BBSRC funding to the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (MR/ K026992/1). Funding Information: Conflict of interest AMM has received financial support from Pfizer (formerly Wyeth), Janssen and Lilly and from the Sackler trust. The remaining authors declare that they have no conflict of interest. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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AU - Wigmore, Eleanor M.

AU - Hafferty, Jonathan D.

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AU - Howard, David M.

AU - Clarke, Toni Kim

AU - Fabbri, Chiara

AU - Lewis, Cathryn M.

AU - Uher, Rudolf

AU - Navrady, Lauren B.

AU - Adams, Mark J.

AU - Zeng, Yanni

AU - Campbell, Archie

AU - Gibson, Jude

AU - Thomson, Pippa A.

AU - Hayward, Caroline

AU - Smith, Blair H.

AU - Hocking, Lynne J.

AU - Padmanabhan, Sandosh

AU - Deary, Ian J.

AU - Porteous, David J.

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AU - Nicodemus, Kristin K.

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PY - 2020/4/1

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Genome-wide association study of antidepressant treatment resistance in a population-based cohort using health service prescription data and meta-analysis with GENDEP

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