A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank
Authors: Shen Xueyi , Howard David M. , Adams Mark J. , Hill W. David , Clarke Toni-Kim ,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Adams Mark J. , Clarke Toni-Kim , McIntosh Andrew M. , Deary Ian J. , Wray Naomi R. , Ripke Stephan , Mattheisen Manuel , Trzaskowski Maciej , Byrne Enda M. , Abdellaoui Abdel , Agerbo Esben , Air Tracy M. , Andlauer Till F. M. , Bacanu Silviu-Alin , Bækvad-Hansen Marie , Beekman Aartjan T. F. , Bigdeli Tim B. , Binder Elisabeth B. , Bryois Julien , Buttenschøn Henriette N. , Bybjerg-Grauholm Jonas , Cai Na , Castelao Enrique , Christensen Jane Hvarregaard , Coleman Jonathan R. I. , Colodro-Conde Lucía , Couvy-Duchesne Baptiste , Craddock Nick , Crawford Gregory E. , Davies Gail , Degenhardt Franziska , Derks Eske M. , Direk Nese , Dolan Conor V. , Dunn Erin C. , Eley Thalia C. , Escott-Price Valentina , Kiadeh Farnush Farhadi Hassan , Finucane Hilary K. , Foo Jerome C. , Forstner Andreas J. , Frank Josef , Gaspar Héléna A. , Gill Michael , Goes Fernando S. , Gordon Scott D. , Grove Jakob , Hall Lynsey S. , Hansen Christine Søholm , Hansen Thomas F. , Herms Stefan , Hickie Ian B. , Hoffmann Per , Homuth Georg , Horn Carsten , Hottenga Jouke-Jan , Hougaard David M. , Howard David M. , Ising Marcus , Jansen Rick , Jones Ian , Jones Lisa A. , Jorgenson Eric , Knowles James A. , Kohane Isaac S. , Kraft Julia , Kretzschmar Warren W. , Kutalik Zoltán , Li Yihan , Lind Penelope A. , MacIntyre Donald J. , MacKinnon Dean F. , Maier Robert M. , Maier Wolfgang , Marchini Jonathan , Mbarek Hamdi , McGrath Patrick , McGuffin Peter , Medland Sarah E. , Mehta Divya , Middeldorp Christel M. , Mihailov Evelin , Milaneschi Yuri , Milani Lili , Mondimore Francis M. , Montgomery Grant W. , Mostafavi Sara , Mullins Niamh , Nauck Matthias , Ng Bernard , Nivard Michel G. , Nyholt Dale R. , O’Reilly Paul F. , Oskarsson Hogni , Owen Michael J. , Painter Jodie N. , Pedersen Carsten Bøcker , Pedersen Marianne Giørtz , Peterson Roseann E. , Pettersson Erik , Peyrot Wouter J. , Pistis Giorgio , Posthuma Danielle , Quiroz Jorge A. , Qvist Per , Rice John P. , Riley Brien P. , Rivera Margarita , Mirza Saira Saeed , Schoevers Robert , Schulte Eva C. , Shen Ling , Shi Jianxin , Shyn Stanley I. , Sigurdsson Engilbert , Sinnamon Grant C. B. , Smit Johannes H. , Smith Daniel J. , Stefansson Hreinn , Steinberg Stacy , Streit Fabian , Strohmaier Jana , Tansey Katherine E. , Teismann Henning , Teumer Alexander , Thompson Wesley , Thomson Pippa A. , Thorgeirsson Thorgeir E. , Traylor Matthew , Treutlein Jens , Trubetskoy Vassily , Uitterlinden Andrés G. , Umbricht Daniel , Auwera Sandra Van der , van Hemert Albert M. , Viktorin Alexander , Visscher Peter M. , Wang Yunpeng , Webb Bradley T. , Weinsheimer Shantel Marie , Wellmann Jürgen , Willemsen Gonneke , Witt Stephanie H. , Wu Yang , Xi Hualin S. , Yang Jian , Zhang Futao , Arolt Volker , Baune Bernhard T. , Berger Klaus , Boomsma Dorret I. , Cichon Sven , Dannlowski Udo , de Geus E. J. C. , DePaulo J. Raymond , Domenici Enrico , Domschke Katharina , Esko Tõnu , Grabe Hans J. , Hamilton Steven P. , Hayward Caroline , Heath Andrew C. , Kendler Kenneth S. , Kloiber Stefan , Lewis Glyn , Li Qingqin S. , Lucae Susanne , Madden Pamela A. F. , Magnusson Patrik K. , Martin Nicholas G. , Metspalu Andres , Mors Ole , Mortensen Preben Bo , Müller-Myhsok Bertram , Nordentoft Merete , Nöthen Markus M. , O’Donovan Michael C. , Paciga Sara A. , Pedersen Nancy L. , Penninx Brenda W. J. H. , Perlis Roy H. , Porteous David J. , Potash James B. , Preisig Martin , Rietschel Marcella , Schaefer Catherine , Schulze Thomas G. , Smoller Jordan W. , Stefansson Kari , Tiemeier Henning , Uher Rudolf , Völzke Henry , Weissman Myrna M. , Werge Thomas , Lewis Cathryn M. , Levinson Douglas F. , Breen Gerome , Børglum Anders D. , Sullivan Patrick F. , Deary Ian J. , Whalley Heather C. , McIntosh Andrew M. 
Published: May 2020

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.