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

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

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

SUNY Downstate Health Sciences University, Upstate Medical University

University of Edinburgh
King's College London
University of Queensland
Massachusetts General Hospital
Charité – Universitätsmedizin Berlin
Broad Institute
University of Würzburg
Karolinska Institutet
Aarhus University
University of Amsterdam
H. Lundbeck A/S
Adelaide University
Max Planck Institute of Psychiatry
Technical University of Munich
Virginia Commonwealth University
Statens Serum Institut
VU. University VU. Medical Center
Emory University
Wellcome Trust Sanger Institute
European Molecular Biology Laboratory
University of Lausanne
Queensland Institute of Medical Research
Cardiff University
Duke University
University of Bonn
Erasmus University Rotterdam
Dokuz Eylul University
University of British Columbia
Harvard University
Massachusetts Institute of Technology
Heidelberg University
University of Basel
University of Marburg
Trinity College Dublin
Johns Hopkins University
NHS in Aberdeen
University of Dundee
King's College London
University of Adelaide
Virginia Institute for Psychiatric and Behavior Genetics
Duke University
University of Bonn
Harvard University
Massachusetts Institute of Technology

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93 Scopus citations

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
Article number	2301
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16022-0
State	Published - Dec 1 2020

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@article{dae08a2bdb284439a0aae6ba8fb6806a,

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

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, pFDR < 0.043). Several behavioural traits are also associated with depression-PRS (β: 0.014 to 0.180, pFDR: 0.049 to 1.28 {\texttimes} 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.",

author = "\{Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium\} and Xueyi Shen and Howard, \{David M.\} and Adams, \{Mark J.\} and Hill, \{W. David\} 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 Forstner, \{Andreas J.\} and Josef Frank and Gaspar, \{H{\'e}l{\'e}na A.\} and Michael Gill and Goes, \{Fernando S.\} and Gordon, \{Scott D.\} and Peterson, \{Roseann E.\} and Schulze, \{Thomas G.\}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-16022-0",

language = "English",

volume = "11",

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TY - JOUR

T1 - A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank

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

AU - Shen, Xueyi

AU - Howard, David M.

AU - Adams, Mark J.

AU - Hill, W. David

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.

AU - Bryois, Julien

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 - Forstner, Andreas J.

AU - Frank, Josef

AU - Gaspar, Héléna A.

AU - Gill, Michael

AU - Goes, Fernando S.

AU - Gordon, Scott D.

AU - Peterson, Roseann E.

AU - Schulze, Thomas G.

PY - 2020/12/1

Y1 - 2020/12/1

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, pFDR < 0.043). Several behavioural traits are also associated with depression-PRS (β: 0.014 to 0.180, pFDR: 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, pFDR < 0.043). Several behavioural traits are also associated with depression-PRS (β: 0.014 to 0.180, pFDR: 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.

UR - https://www.scopus.com/pages/publications/85084721245

U2 - 10.1038/s41467-020-16022-0

DO - 10.1038/s41467-020-16022-0

M3 - Article

C2 - 32385265

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2301

ER -

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

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