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Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

By Naomi R. Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski, Enda M. Byrne, Abdel Abdellaoui, Mark J Adams, Esben Agerbo, Tracy M Air, Till F. M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T F Beekman, Tim B Bigdeli, Elisabeth B. Binder, Douglas H R Blackwood, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Toni-Kim Clarke, Jonathan R. I. Coleman, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Cheynna A Crowley, Hassan S Dashti, Gail Davies, Ian J Deary, Franziska Degenhardt, Eske M Derks, Nese Direk, Conor V. Dolan, Erin C Dunn, Thalia C Eley, Nicholas Eriksson, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K Finucane, Andreas J. Forstner, Josef Frank, Héléna A Gaspar, Michael Gill, Paola Giusti-Rorínguez, Fernando S. Goes, Scott D Gordon, Jakob Grove, Lynsey S Hall, Christine Søholm Hansen, Thomas F Hansen, Stefan Herms, Ian B Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M Hougaard, Ming Hu, Craig L Hyde, Marcus Ising, Rick Jansen, Fulai Jin, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Jesper Krogh, Zoltan Kutalik, Jacqueline M. Lane, Yihan Li, Yun Li, Penelope A Lind, Xiaoxiao Liu, Leina Lu, Donald J MacIntyre, Dean F MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Patrick 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, Hogni Oskarsson, Michael J Owen, Jodie N Painter, Carsten Bøcker, Marianne Giørtz Pedersen, Roseann E. Peterson, Erik Pettersson, Wouter J Peyrot, Giorgio Pistis, Danielle Posthuma, Shaun M. Purcell, Jorge A Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Margarita Rivera, Saira Saeed Mirza, Richa Saxena, Robert Schoevers, Eva C Schulte, Ling Shen, Jianxin Shi, Stanley I Shyn, Engilbert Sigurdsson, Grant C B Sinnamon, Johannes H Smit, Daniel J Smith, Hreinn Stefansson, Stacy Steinberg, Craig A. Stockmeier, Fabian Streit, Jana Strohmaier, Katherine E Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa a Thomson, Thorgeir E. Thorgeirsson, Chao Tian, 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 Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin S Xi, Jian Yang, Futao Zhang, eQTLGen Consortium, 23andMe Research Team, Volker Arolt, Bernhard T. Baune, Klaus Berger, Dorret I Boomsma, Sven Cichon, udo Dannlowski, EJC de Geus, J. Raymond DePaulo, Enrico Domenici, Katharina Domschke, Tönu Esko, Hans J Grabe, Steven P Hamilton, Caroline Hayward, Andrew C Heath, David A. Hinds, Kenneth S. Kendler, Stefan Kloiber, Glyn Lewis, Qingqin S Li, Susanne Lucae, Pamela A.F. Madden, Patrik K Magnusson, Nicholas G Martin, Andrew M McIntosh, Andres Metspalu, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Merete Nordentoft, Markus M Nöthen, Michael C 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, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Henry Völzke, Myrna M. Weissman, Thomas Werge, Ashley R Winslow, Cathryn M Lewis, Douglas F. Levinson, Gerome Breen, Anders D. Børglum, Patrick F Sullivan, for the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Posted 24 Jul 2017
bioRxiv DOI: 10.1101/167577 (published DOI: 10.1038/s41588-018-0090-3)

Major depressive disorder (MDD) is a notably complex illness with a lifetime prevalence of 14%. 1 It is often chronic or recurrent and is thus accompanied by considerable morbidity, excess mortality, substantial costs, and heightened risk of suicide. 2-7 MDD is a major cause of disability worldwide. 8 We conducted a genome-wide association (GWA) meta-analysis in 130,664 MDD cases and 330,470 controls, and identified 44 independent loci that met criteria for statistical significance. We present extensive analyses of these results which provide new insights into the nature of MDD. The genetic findings were associated with clinical features of MDD, and implicated prefrontal and anterior cingulate cortex in the pathophysiology of MDD (regions exhibiting anatomical differences between MDD cases and controls). Genes that are targets of antidepressant medications were strongly enriched for MDD association signals (P=8.5x10-10), suggesting the relevance of these findings for improved pharmacotherapy of MDD. Sets of genes involved in gene splicing and in creating isoforms were also enriched for smaller MDD GWA P-values, and these gene sets have also been implicated in schizophrenia and autism. Genetic risk for MDD was correlated with that for many adult and childhood onset psychiatric disorders. Our analyses suggested important relations of genetic risk for MDD with educational attainment, body mass, and schizophrenia: the genetic basis of lower educational attainment and higher body mass were putatively causal for MDD whereas MDD and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for MDD, and a continuous measure of risk underlies the observed clinical phenotype. MDD is not a distinct entity that neatly demarcates normalcy from pathology but rather a useful clinical construct associated with a range of adverse outcomes and the end result of a complex process of intertwined genetic and environmental effects. These findings help refine and define the fundamental basis of MDD.

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