Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Aleix Arnau-Soler; Mark J. Adams; Generation Scotland; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Caroline Hayward; Pippa A. Thomson; David Porteous; Archie Campbell; Blair H. Smith; Corri Black; Sandosh Padmanabhan; Andrew M. McIntosh; Naomi R. Wray; Stephan Ripke; Manuel Mattheisen; Maciej Trzaskowski; Enda M. Byrne; Abdel Abdellaoui; Esben Agerbo; Tracy M. Air; Till F.M. Andlauer; Silviu Alin Bacanu; Marie Bækvad-Hansen; Aartjan T.F. Beekman; Tim B. Bigdeli; Elisabeth B. Binder; Douglas H.R. Blackwood; Julien Bryois; Henriette N. Buttenschøn; Jonas Bybjerg-Grauholm; Na Cai; Enrique Castelao; Jane Hvarregaard Christensen; Toni Kim Clarke; Jonathan R.I. Coleman; Lucía Colodro-Conde; Baptiste Couvy-Duchesne; Nick Craddock; Gregory E. Crawford; Gail Davies; Ian J. Deary; Franziska Degenhardt; Eske M. Derks; Nese Direk; Conor V. Dolan; Christine Søholm Hansen; Thomas F. Hansen; Jesper Krogh; Carsten Bøcker Pedersen; Marianne Giørtz Pedersen; Merete Nordentoft; Thomas Werge

doi:10.1371/journal.pone.0209160

Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Aleix Arnau-Soler^*, Mark J. Adams, Generation Scotland, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Caroline Hayward, Pippa A. Thomson, David Porteous, Archie Campbell, Blair H. Smith, Corri Black, Sandosh Padmanabhan, Andrew M. McIntosh, Naomi R. Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski, Enda M. Byrne, Abdel Abdellaoui, Esben Agerbo, Tracy M. AirTill F.M. Andlauer, Silviu Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Tim B. Bigdeli, Elisabeth B. Binder, Douglas H.R. Blackwood, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Toni Kim Clarke, Jonathan R.I. Coleman, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Ian J. Deary, Franziska Degenhardt, Eske M. Derks, Nese Direk, Conor V. Dolan, Christine Søholm Hansen, Thomas F. Hansen, Jesper Krogh, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Merete Nordentoft, Thomas Werge

^*Corresponding author for this work

Department of Clinical Medicine

2 Citations (Scopus)

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Abstract

Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48×10 ^-7 ; Bonferroni-corrected significance threshold p < 2.79×10 ^-6 ). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity.

Original language	English
Article number	e0209160
Journal	PLOS ONE
Volume	13
Issue number	12
Pages (from-to)	1-29
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0209160
Publication status	Published - 2018

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Arnau-Soler, A., Adams, M. J., Generation Scotland, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Hayward, C., Thomson, P. A., Porteous, D., Campbell, A., Smith, B. H., Black, C., Padmanabhan, S., McIntosh, A. M., Wray, N. R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E. M., Abdellaoui, A., Agerbo, E., ... Werge, T. (2018). Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder. PLOS ONE, 13(12), 1-29. [e0209160]. https://doi.org/10.1371/journal.pone.0209160

Arnau-Soler, A, Adams, MJ, Generation Scotland, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Hayward, C, Thomson, PA, Porteous, D, Campbell, A, Smith, BH, Black, C, Padmanabhan, S, McIntosh, AM, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, SA, Bækvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschøn, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, TK, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Hansen, CS, Hansen, TF, Krogh, J, Pedersen, CB, Pedersen, MG, Nordentoft, M & Werge, T 2018, 'Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder', PLOS ONE, vol. 13, no. 12, e0209160, pp. 1-29. https://doi.org/10.1371/journal.pone.0209160

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title = "Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder",

abstract = " Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48×10 -7 ; Bonferroni-corrected significance threshold p < 2.79×10 -6 ). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity. ",

author = "Aleix Arnau-Soler and Adams, {Mark J.} and {Generation Scotland} and {Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium} and Caroline Hayward and Thomson, {Pippa A.} and David Porteous and Archie Campbell and Smith, {Blair H.} and Corri Black and Sandosh Padmanabhan and McIntosh, {Andrew M.} and Wray, {Naomi R.} and Stephan Ripke and Manuel Mattheisen and Maciej Trzaskowski and Byrne, {Enda M.} and Abdel Abdellaoui and Esben Agerbo and Air, {Tracy M.} and Andlauer, {Till F.M.} and Bacanu, {Silviu Alin} and Marie B{\ae}kvad-Hansen and Beekman, {Aartjan T.F.} and Bigdeli, {Tim B.} and Binder, {Elisabeth B.} and Blackwood, {Douglas H.R.} and Julien Bryois and Buttensch{\o}n, {Henriette N.} and Jonas Bybjerg-Grauholm and Na Cai and Enrique Castelao and Christensen, {Jane Hvarregaard} and Clarke, {Toni Kim} and Coleman, {Jonathan R.I.} and Luc{\'i}a Colodro-Conde and Baptiste Couvy-Duchesne and Nick Craddock and Crawford, {Gregory E.} and Gail Davies and Deary, {Ian J.} and Franziska Degenhardt and Derks, {Eske M.} and Nese Direk and Dolan, {Conor V.} and Hansen, {Christine S{\o}holm} and Hansen, {Thomas F.} and Jesper Krogh and Pedersen, {Carsten B{\o}cker} and Pedersen, {Marianne Gi{\o}rtz} and Merete Nordentoft and Thomas Werge",

year = "2018",

doi = "10.1371/journal.pone.0209160",

language = "English",

volume = "13",

pages = "1--29",

journal = "PLoS Computational Biology",

issn = "1932-6203",

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T1 - Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

AU - Arnau-Soler, Aleix

AU - Adams, Mark J.

AU - Generation Scotland

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - Hayward, Caroline

AU - Thomson, Pippa A.

AU - Porteous, David

AU - Campbell, Archie

AU - Smith, Blair H.

AU - Black, Corri

AU - Padmanabhan, Sandosh

AU - McIntosh, Andrew M.

AU - Wray, Naomi R.

AU - Ripke, Stephan

AU - Mattheisen, Manuel

AU - Trzaskowski, Maciej

AU - Byrne, Enda M.

AU - Abdellaoui, Abdel

AU - Agerbo, Esben

AU - Air, Tracy M.

AU - Andlauer, Till F.M.

AU - Bacanu, Silviu Alin

AU - Bækvad-Hansen, Marie

AU - Beekman, Aartjan T.F.

AU - Bigdeli, Tim B.

AU - Binder, Elisabeth B.

AU - Blackwood, Douglas H.R.

AU - Bryois, Julien

AU - Buttenschøn, Henriette N.

AU - Bybjerg-Grauholm, Jonas

AU - Cai, Na

AU - Castelao, Enrique

AU - Christensen, Jane Hvarregaard

AU - Clarke, Toni Kim

AU - Coleman, Jonathan R.I.

AU - Colodro-Conde, Lucía

AU - Couvy-Duchesne, Baptiste

AU - Craddock, Nick

AU - Crawford, Gregory E.

AU - Davies, Gail

AU - Deary, Ian J.

AU - Degenhardt, Franziska

AU - Derks, Eske M.

AU - Direk, Nese

AU - Dolan, Conor V.

AU - Hansen, Christine Søholm

AU - Hansen, Thomas F.

AU - Krogh, Jesper

AU - Pedersen, Carsten Bøcker

AU - Pedersen, Marianne Giørtz

AU - Nordentoft, Merete

AU - Werge, Thomas

PY - 2018

Y1 - 2018

N2 - Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48×10 -7 ; Bonferroni-corrected significance threshold p < 2.79×10 -6 ). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity.

AB - Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48×10 -7 ; Bonferroni-corrected significance threshold p < 2.79×10 -6 ). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity.

U2 - 10.1371/journal.pone.0209160

DO - 10.1371/journal.pone.0209160

M3 - Journal article

C2 - 30571770

AN - SCOPUS:85058923883

SN - 1932-6203

VL - 13

SP - 1

EP - 29

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 12

M1 - e0209160

ER -

Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

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