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

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 Medical Center
Virginia Institute for Psychiatric and Behavior Genetics
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
Newcastle University
University of Copenhagen
Mental Health Services Capital Region of Denmark
The University of Sydney
University of Greifswald
F. Hoffmann-La Roche AG
University of Worcester
Kaiser Permanente
University of Southern California
Brigham and Women’s Hospital
Boston Children's Hospital
University of Oxford
Swiss Institute of Bioinformatics
National Health Service Scotland
Columbia University
Queensland University of Technology
Children’s Health Queensland
University of Tartu
German Centre for Cardiovascular Research
Humus Inc
Vrije Universiteit Amsterdam
Solid Biosciences
Washington University St. Louis
University of Granada
University of Groningen
Ludwig Maximilian University of Munich
National Institutes of Health
University of Iceland
James Cook University Queensland
University of Glasgow
deCODE Genetics
University of Münster
University of California at San Diego
University of Oslo
University of Cambridge
Leiden University
Pfizer
University of Melbourne
Jülich Research Centre
University of Trento
University of Freiburg
University of Toronto
University College London
Johnson & Johnson
University of Tartu
Munich Cluster for Systems Neurology (SyNergy)
University of Liverpool
University of Iowa
University of Göttingen
Dalhousie University
Stanford University
University of North Carolina at Chapel Hill

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

87 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
Article number	2301
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16022-0
Publication status	Published - 1 Dec 2020
Externally published	Yes

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10.1038/s41467-020-16022-0

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@article{18c5ea3e1b164aad8f1f384a596f7d66,

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 × 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 Hottenga, \{Jouke Jan\}",

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",

journal = "Nature Communications",

issn = "2041-1723",

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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 - Hottenga, Jouke Jan

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

AN - SCOPUS:85084721245

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

Abstract

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