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

2020; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41467-020-16022-0

2041-1723

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 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 Christensen, Jonathan R. I. Coleman, Lucía Colodro‐Conde, Baptiste Couvy‐Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Franziska Degenhardt, Eske M. Derks, Neşe Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott‐Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Andreas J. Forstner, Josef Frank, Helena Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas Hansen, Stefan Herms, Ian B. Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke‐Jan Hottenga, David M. Hougaard, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa Jones, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Patrick J. McGrath, Peter McGuffin, Sarah E. Medland, Divya Mehta, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Högni Óskarsson, Michael J. Owen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Erik Pettersson, Wouter J. Peyrot, Giorgio Pistis, Daniëlle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Margarita Rivera, Saira Saeed Mirza, Robert A. Schoevers, Eva C. Schulte, Ling Shen, Jianxin Shi, Stanley I. Shyn, Engilbert Sigurðsson, Grant Sinnamon, Johannes H. Smit, Daniel J. Smıth, Hreinn Stefánsson, Stacy Steinberg, Fabian Streit, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Shantel Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin Simon Xi, Jian Yang, Futao Zhang, Volker Arolt, Bernhard T. Baune, Klaus Peter Berger, Dorret I. Boomsma, Sven Cichon, Udo Dannlowski, Eco J. C. de Geus, J. Raymond DePaulo, Enrico Domenici, Katharina Domschke, Tõnu Esko, Hans J. Grabe, Steven P. Hamilton, Caroline Hayward, Andrew C. Heath, Kenneth S. Kendler, Stefan Kloiber, Glyn Lewis, Qingqin S. Li, Susanne Lucae, Pamela A. F. Madden, Patrik K. E. Magnusson, Nicholas G. Martin, Andres Metspalu, Ole Mors, Preben Bo Mortensen, Bertram Müller‐Myhsok, Merete Nordentoft, Markus M. Nöthen, Michael O’Donovan, Sara A. Paciga, Nancy L. Pedersen, Brenda W.J.H. Penninx, Roy H. Perlis, David J. Porteous, James B. Potash, Martin Preisig, Marcella Rietschel, Catherine Schaefer, Thomas G. Schulze, Jordan W. Smoller, Hreinn Stefánsson, Henning Tiemeier, Rudolf Uher, Henry Völzke, Myrna M. Weissman, Thomas Werge, Cathryn M. Lewis, Douglas F. Levinson, Gerome Breen, Anders D. Børglum, Patrick F. Sullivan, Ian J. Deary, Heather C. Whalley, Andrew M. McIntosh,

Health, Environment, Cognitive Aging

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.