A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank
Xueyi Shen(University of Edinburgh), David M. Howard(King's College London), Mark J. Adams(University of Edinburgh), W. David Hill(University of Edinburgh), Toni-Kim Clarke(University of Edinburgh), Mark J. Adams(University of Edinburgh), Toni‐Kim Clarke(University of Edinburgh), Andrew M. McIntosh(Alzheimer Scotland), Ian J. Deary(University of Edinburgh), Naomi R. Wray(The University of Queensland), Stephan Ripke(Broad Institute), Manuel Mattheisen(Aarhus University), Maciej Trzaskowski(The University of Queensland), Enda M. Byrne(The University of Queensland), Abdel Abdellaoui(Amsterdam Public Health), Esben Agerbo(Aarhus University), Tracy Air(The University of Adelaide), Till F. M. Andlauer(TUM Klinikum), Silviu‐Alin Bacanu(Virginia Commonwealth University), Marie Bækvad‐Hansen(Statens Serum Institut), Aartjan T.F. Beekman(GGZ inGeest), Tim B. Bigdeli(Genetics and IVF Institute), Elisabeth B. Binder(Emory University), Julien Bryois(Karolinska Institutet), Henriette N. Buttenschøn(Aarhus University), Jonas Bybjerg‐Grauholm(Statens Serum Institut), Na Cai(European Bioinformatics Institute), Enrique Castelao(University Hospital of Lausanne), Jane Christensen(Aarhus University), Jonathan R. I. Coleman(King's College London), Lucía Colodro‐Conde(QIMR Berghofer Medical Research Institute), Baptiste Couvy‐Duchesne(The University of Queensland), Nick Craddock(Cardiff University), Gregory E. Crawford(Duke University), Gail Davies(University of Edinburgh), Franziska Degenhardt(University of Bonn), Eske M. Derks(QIMR Berghofer Medical Research Institute), Neşe Direk(Dokuz Eylül University), Conor V. Dolan(Amsterdam Public Health), Erin C. Dunn(Broad Institute), Thalia C. Eley(King's College London), Valentina Escott‐Price(Cardiff University), Farnush Farhadi Hassan Kiadeh(University of British Columbia), Hilary K. Finucane(Harvard University), Jerome C. Foo(Heidelberg University), Andreas J. Forstner(University of Bonn), Josef Frank(Heidelberg University), Helena Gaspar(King's College London), Michael Gill(Trinity College Dublin), Fernando S. Goes(Johns Hopkins University), Scott D. Gordon(QIMR Berghofer Medical Research Institute), Jakob Grove(Aarhus University), Lynsey S. Hall(Newcastle University), Christine Søholm Hansen(Statens Serum Institut), Thomas Folkmann Hansen(Mental Health Services), Stefan Herms(University of Bonn), Ian B. Hickie(The University of Sydney), Per Hoffmann(University of Bonn), Georg Homuth(Universität Greifswald), Carsten Horn(Roche (Switzerland)), Jouke‐Jan Hottenga(Amsterdam Public Health), David M. Hougaard(Amsterdam Public Health), David M. Howard(King's College London), Marcus Ising(Max Planck Institute of Psychiatry), Rick Jansen(GGZ inGeest), Ian Jones(Cardiff University), Lisa Jones(University of Worcester), Eric Jorgenson(Kaiser Permanente), James A. Knowles(University of Southern California), Isaac S. Kohane(Brigham and Women's Hospital), Julia Kraft(Charité - Universitätsmedizin Berlin), Warren W. Kretzschmar(Centre for Human Genetics), Zoltán Kutalik(SIB Swiss Institute of Bioinformatics), Yihan Li(Centre for Human Genetics), Penelope A. Lind(QIMR Berghofer Medical Research Institute), Donald J. MacIntyre(Public Health Scotland), Dean F. MacKinnon(Johns Hopkins University), Robert Maier(The University of Queensland), Wolfgang Maier(University of Bonn), Jonathan Marchini(University of Oxford), Hamdi Mbarek(Amsterdam Public Health), Patrick J. McGrath(Columbia University), Peter McGuffin(King's College London), Sarah E. Medland(QIMR Berghofer Medical Research Institute), Divya Mehta(Queensland University of Technology), Christel M. Middeldorp(The University of Queensland), Evelin Mihailov(University of Tartu), Yuri Milaneschi(GGZ inGeest), Lili Milani(University of Tartu), Francis M. Mondimore(Johns Hopkins University), Grant W. Montgomery(The University of Queensland), Sara Mostafavi(University of British Columbia), Niamh Mullins(King's College London), Matthias Nauck(Universitätsmedizin Greifswald), Bernard Ng(University of British Columbia), Michel G. Nivard(Amsterdam Public Health), Dale R. Nyholt(Queensland University of Technology), Paul F. O’Reilly(King's College London), Högni Óskarsson, Michael J. Owen(Cardiff University), Jodie N. Painter(QIMR Berghofer Medical Research Institute), Carsten Bøcker Pedersen(Aarhus University), Marianne Giørtz Pedersen(Aarhus University), Roseann E. Peterson(Virginia Commonwealth University), Erik Pettersson(Karolinska Institutet), Wouter J. Peyrot(GGZ inGeest), Giorgio Pistis(University Hospital of Lausanne), Daniëlle Posthuma(Vrije Universiteit Amsterdam), Jorge A. Quiroz(Solidus Biosciences (United States)), Per Qvist(Aarhus University), John P. Rice(Washington University in St. Louis), Brien P. Riley(Virginia Commonwealth University), Margarita Rivera(Universidad de Granada), Saira Saeed Mirza(Erasmus MC), Robert A. Schoevers(University Medical Center Groningen), Eva C. Schulte(Ludwig-Maximilians-Universität München), Ling Shen(Kaiser Permanente), Jianxin Shi(National Cancer Institute), Stanley I. Shyn(Kaiser Permanente), Engilbert Sigurðsson(University of Iceland), Grant Sinnamon(James Cook University), Johannes H. Smit(GGZ inGeest), Daniel J. Smıth(University of Glasgow), Hreinn Stefánsson(deCODE Genetics (Iceland)), Stacy Steinberg(deCODE Genetics (Iceland)), Fabian Streit(Heidelberg University), Jana Strohmaier(Heidelberg University), Katherine E. Tansey(Cardiff University), Henning Teismann(University of Münster), Alexander Teumer(Universitätsmedizin Greifswald), Wesley Thompson(Oslo University Hospital), Pippa A. Thomson(University of Edinburgh), Thorgeir E. Thorgeirsson(deCODE Genetics (Iceland)), Matthew Traylor(University of Cambridge), Jens Treutlein(Heidelberg University), Vassily Trubetskoy(Charité - Universitätsmedizin Berlin), André G. Uitterlinden(Erasmus MC), Daniel Umbricht(Roche (Switzerland)), Sandra Van der Auwera(Universitätsmedizin Greifswald), Albert M. van Hemert(Leiden University Medical Center), Alexander Viktorin(Karolinska Institutet), Peter M. Visscher(The University of Queensland), Yunpeng Wang(Oslo University Hospital), Bradley T. Webb(Virginia Commonwealth University), Shantel Weinsheimer(Mental Health Services), Jürgen Wellmann(University of Münster), Gonneke Willemsen(Amsterdam Public Health), Stephanie H. Witt(Heidelberg University), Yang Wu(The University of Queensland), Hualin Simon Xi(Pfizer (United States)), Jian Yang(The University of Queensland), Futao Zhang(The University of Queensland), Volker Arolt(University of Münster), Bernhard T. Baune(The University of Melbourne), Klaus Peter Berger(University of Münster), Dorret I. Boomsma(Amsterdam Public Health), Sven Cichon(University of Bonn), Udo Dannlowski(University of Münster), Eco J. C. de Geus(Amsterdam Public Health), J. Raymond DePaulo(Johns Hopkins University), Enrico Domenici(University of Trento), Katharina Domschke(University of Freiburg), Tõnu Esko(Broad Institute), Hans J. Grabe(Universitätsmedizin Greifswald), Steven P. Hamilton(Kaiser Permanente), Caroline Hayward(Institute of Genetics and Cancer), Andrew C. Heath(Washington University in St. Louis), Kenneth S. Kendler(Virginia Commonwealth University), Stefan Kloiber(Centre for Addiction and Mental Health), Glyn Lewis(University College London), Qingqin S. Li(Janssen (United States)), Susanne Lucae(Max Planck Institute of Psychiatry), Pamela A. F. Madden(Washington University in St. Louis), Patrik K. E. Magnusson(Karolinska Institutet), Nicholas G. Martin(QIMR Berghofer Medical Research Institute), Andres Metspalu(University of Tartu), Ole Mors(Aarhus University Hospital), Preben Bo Mortensen(Aarhus University), Bertram Müller‐Myhsok(University of Liverpool), Merete Nordentoft(Copenhagen University Hospital), Markus M. Nöthen(University of Bonn), Michael O‘Donovan(Cardiff University), Sara A. Paciga(Pfizer (United States)), Nancy L. Pedersen(Karolinska Institutet), Brenda W.J.H. Penninx(GGZ inGeest), Roy H. Perlis(Harvard University), David J. Porteous(University of Edinburgh), James B. Potash(University of Iowa), Martin Preisig(University Hospital of Lausanne), Marcella Rietschel(Heidelberg University), Catherine Schaefer(Kaiser Permanente), Thomas G. Schulze(Johns Hopkins University), Jordan W. Smoller(Broad Institute), Kari Stefansson(deCODE Genetics (Iceland)), Henning Tiemeier(Erasmus MC), Rudolf Uher(Dalhousie University), Henry Völzke(Universitätsmedizin Greifswald), Myrna M. Weissman(New York Psychoanalytic Society and Institute), Thomas Werge(University of Copenhagen), Cathryn M. Lewis(King's College London), Douglas F. Levinson(Stanford University), Gerome Breen(King's College London), Anders D. Børglum(Aarhus University), Patrick F. Sullivan(University of North Carolina at Chapel Hill), Ian J. Deary(University of Edinburgh), Heather C. Whalley(University of Edinburgh), Andrew M. McIntosh(Alzheimer Scotland)
Cited by 124Open Access
Abstract
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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