A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank

Xueyi Shen; David M. Howard; Mark J. Adams; W. David Hill; Toni Kim Clarke; Mark J. Adams; Toni Kim Clarke; Andrew M. McIntosh; Ian J. Deary; 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; Julien Bryois; Henriette N. Buttenschøn; Jonas Bybjerg-Grauholm; Na Cai; Enrique Castelao; Jane Hvarregaard Christensen; Jonathan R.I. Coleman; Lucía Colodro-Conde; Baptiste Couvy-Duchesne; Nick Craddock; Gregory E. Crawford; Gail Davies; Franziska Degenhardt; Eske M. Derks; Nese Direk; Conor V. Dolan; Erin C. Dunn; Thalia C. Eley; Valentina Escott-Price; Farnush Farhadi Hassan Kiadeh; Hilary K. Finucane; Jerome C. Foo; Thomas F. Hansen; Wesley Thompson; Shantel Marie Weinsheimer; Merete Nordentoft; Thomas Werge; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

doi:10.1038/s41467-020-16022-0

A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank

Xueyi Shen, David M. Howard, Mark J. Adams, W. David Hill, Toni Kim Clarke, Mark J. Adams, Toni Kim Clarke, Andrew M. McIntosh, Ian J. Deary, 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-HansenAartjan T.F. Beekman, Tim B. Bigdeli, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Jonathan R.I. Coleman, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Franziska Degenhardt, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Thomas F. Hansen, Wesley Thompson, Shantel Marie Weinsheimer, Merete Nordentoft, Thomas Werge, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

70 Citations (Scopus)

Abstract

Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N = 10,674) and replication (N = 11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (β: 0.125 to 0.868, p FDR < 0.043). Several behavioural traits are also associated with depression-PRS (β: 0.014 to 0.180, p FDR: 0.049 to 1.28 × 10 -14) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression.

Original language	English
Journal	Nature Communications
Volume	11
Issue number	1
Pages (from-to)	2301
ISSN	2041-1722
DOIs	https://doi.org/10.1038/s41467-020-16022-0
Publication status	Published - 8 May 2020

Keywords

Aged
Biological Specimen Banks
Depression/genetics
Female
Genetic Predisposition to Disease/genetics
Genome-Wide Association Study
Humans
Male
Mendelian Randomization Analysis
Middle Aged
Neuroimaging/methods
Polymorphism, Single Nucleotide/genetics
Prefrontal Cortex/metabolism
Risk Factors

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10.1038/s41467-020-16022-0

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Shen, X., Howard, D. M., Adams, M. J., Hill, W. D., Clarke, T. K., Adams, M. J., Clarke, T. K., McIntosh, A. M., Deary, I. J., Wray, N. R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E. M., Abdellaoui, A., Agerbo, E., Air, T. M., Andlauer, T. F. M., Bacanu, S. A., ... Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (2020). A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank. Nature Communications, 11(1), 2301. https://doi.org/10.1038/s41467-020-16022-0

Shen, X, Howard, DM, Adams, MJ, Hill, WD, Clarke, TK, Adams, MJ, Clarke, TK, McIntosh, AM, Deary, IJ, 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, Bryois, J, Buttenschøn, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Hansen, TF , Thompson, W, Weinsheimer, SM, Nordentoft, M , Werge, T & Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium 2020, 'A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank', Nature Communications, vol. 11, no. 1, pp. 2301. https://doi.org/10.1038/s41467-020-16022-0

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abstract = "Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N = 10,674) and replication (N = 11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (β: 0.125 to 0.868, p FDR < 0.043). Several behavioural traits are also associated with depression-PRS (β: 0.014 to 0.180, p FDR: 0.049 to 1.28 × 10 -14) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression. ",

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author = "Xueyi Shen and Howard, {David M.} and Adams, {Mark J.} and Hill, {W. David} and Clarke, {Toni Kim} and Adams, {Mark J.} and Clarke, {Toni Kim} and McIntosh, {Andrew M.} and Deary, {Ian J.} 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 Julien Bryois and Buttensch{\o}n, {Henriette N.} and Jonas Bybjerg-Grauholm and Na Cai and Enrique Castelao and Christensen, {Jane Hvarregaard} 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 Franziska Degenhardt and Derks, {Eske M.} and Nese Direk and Dolan, {Conor V.} and Dunn, {Erin C.} and Eley, {Thalia C.} and Valentina Escott-Price and Kiadeh, {Farnush Farhadi Hassan} and Finucane, {Hilary K.} and Foo, {Jerome C.} and Hansen, {Thomas F.} and Wesley Thompson and Weinsheimer, {Shantel Marie} and Merete Nordentoft and Thomas Werge and {Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium}",

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AU - Shen, Xueyi

AU - Howard, David M.

AU - Adams, Mark J.

AU - Hill, W. David

AU - Clarke, Toni Kim

AU - Adams, Mark J.

AU - Clarke, Toni Kim

AU - McIntosh, Andrew M.

AU - Deary, Ian J.

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.

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AU - Buttenschøn, Henriette N.

AU - Bybjerg-Grauholm, Jonas

AU - Cai, Na

AU - Castelao, Enrique

AU - Christensen, Jane Hvarregaard

AU - Coleman, Jonathan R.I.

AU - Colodro-Conde, Lucía

AU - Couvy-Duchesne, Baptiste

AU - Craddock, Nick

AU - Crawford, Gregory E.

AU - Davies, Gail

AU - Degenhardt, Franziska

AU - Derks, Eske M.

AU - Direk, Nese

AU - Dolan, Conor V.

AU - Dunn, Erin C.

AU - Eley, Thalia C.

AU - Escott-Price, Valentina

AU - Kiadeh, Farnush Farhadi Hassan

AU - Finucane, Hilary K.

AU - Foo, Jerome C.

AU - Hansen, Thomas F.

AU - Thompson, Wesley

AU - Weinsheimer, Shantel Marie

AU - Nordentoft, Merete

AU - Werge, Thomas

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

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N2 - Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N = 10,674) and replication (N = 11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (β: 0.125 to 0.868, p FDR < 0.043). Several behavioural traits are also associated with depression-PRS (β: 0.014 to 0.180, p FDR: 0.049 to 1.28 × 10 -14) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression.

AB - Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N = 10,674) and replication (N = 11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (β: 0.125 to 0.868, p FDR < 0.043). Several behavioural traits are also associated with depression-PRS (β: 0.014 to 0.180, p FDR: 0.049 to 1.28 × 10 -14) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression.

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KW - Depression/genetics

KW - Female

KW - Genetic Predisposition to Disease/genetics

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Mendelian Randomization Analysis

KW - Middle Aged

KW - Neuroimaging/methods

KW - Polymorphism, Single Nucleotide/genetics

KW - Prefrontal Cortex/metabolism

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JO - Nature Communications

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ER -

A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank

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Keywords

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