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

Authors
Naomi Wray,Stephan Ripke
Manuel Mattheisen,Maciej Trzaskowski,Enda Byrne,Abdel Abdellaoui,Mark Adams,Esben Agerbo,Tracy Air,Till Andlauer,Silviu-Alin Bacanu,Marie Bækvad-Hansen,Aartjan Beekman,Tim Bigdeli,Elisabeth Binder,Douglas Blackwood,Julien Bryois,Henriette Buttenschøn,Jonas Bybjerg-Grauholm,Na Cai,Enrique Castelao,Jane Christensen,Toni-Kim Clarke,Jonathan Coleman,Lucía Colodro-Conde,Baptiste Couvy-Duchesne,Nick Craddock,Gregory Crawford,Cheynna Crowley,Hassan Dashti,Gail Davies,Ian Deary,Franziska Degenhardt,Eske Derks,Nese Direk,Conor Dolan,Erin Dunn,Thalia Eley,Nicholas Eriksson,Valentina Escott-Price,Farnush Kiadeh,Hilary Finucane,Andreas Forstner,Josef Frank,Héléna Gaspar,Michael Gill,Paola Giusti-Rorínguez,Fernando Goes,Scott Gordon,Jakob Grove,Lynsey Hall,Christine Hansen,Thomas Hansen,Stefan Herms,Ian Hickie,Per Hoffmann,Georg Homuth,Carsten Horn,Jouke-Jan Hottenga,David Hougaard,Ming Hu,Craig Hyde,Marcus Ising,Rick Jansen,Fulai Jin,Eric Jorgenson,James Knowles,Isaac Kohane,Julia Kraft,Warren Kretzschmar,Jesper Krogh,Zoltan Kutalik,Jacqueline Lane,Yihan Li,Yun Li,Penelope Lind,Xiaoxiao Liu,Leina Lu,Donald MacIntyre,Dean MacKinnon,Robert Maier,Wolfgang Maier,Jonathan Marchini,Hamdi Mbarek,Patrick McGrath,Peter McGuffin,Sarah Medland,Divya Mehta,Christel Middeldorp,Evelin Mihailov,Yuri Milaneschi,Lili Milani,Francis Mondimore,Grant Montgomery,Sara Mostafavi,Niamh Mullins,Matthias Nauck,Bernard Ng,Mark Fontana,Dale Nyholt,Paul O'Reilly,Hogni Oskarsson,Michael Owen,Jodie Painter,Carsten Bøcker,Marianne Pedersen,Roseann Peterson,Erik Pettersson,Wouter Peyrot,Giorgio Pistis,Danielle Posthuma,Shaun Purcell,Jorge Quiroz,Per Qvist,John Rice,Brien Riley,Margarita Rivera,Saira Mirza,Richa Saxena,Robert Schoevers,Eva Schulte,Ling Shen,Jianxin Shi,Stanley Shyn,Engilbert Sigurdsson,Grant Sinnamon,Johannes Smit,Daniel Smith,Hreinn Stefansson,Stacy Steinberg,Craig Stockmeier,Fabian Streit,Jana Strohmaier,Katherine Tansey,Henning Teismann,Alexander Teumer,Wesley Thompson,Pippa Thomson,Thorgeir Thorgeirsson,Chao Tian,Matthew Traylor,Jens Treutlein,Vassily Trubetskoy,André Uitterlinden,Daniel Umbricht,Sandra Auwera,Albert Hemert,Alexander Viktorin,Peter Visscher,Yunpeng Wang,Bradley Webb,Shantel Weinsheimer,Jürgen Wellmann,Gonneke Willemsen,Stephanie Witt,Yang Wu,Hualin Xi,Jian Yang,Futao Zhang,eQTLGen Consortium,23andMe Team,Volker Arolt,Bernhard Baune,Klaus Berger,Dorret Boomsma,Sven Cichon,Udo Dannlowski,EJC Geus,J. DePaulo,Enrico Domenici,Katharina Domschke,Tönu Esko,Hans Grabe,Steven Hamilton,Caroline Hayward,Andrew Heath,David Hinds,Kenneth Kendler,Stefan Kloiber,Glyn Lewis,Qingqin Li,Susanne Lucae,Pamela Madden,Patrik Magnusson,Nicholas Martin,Y Zeng,Andres Metspalu,Ole Mors,Preben Mortensen,Bertram Müller-Myhsok,Merete Nordentoft,Markus Nöthen,Michael O'Donovan,Sara Paciga,Nancy Pedersen,Brenda Penninx,Roy Perlis,David Porteous,James Potash,Martin Preisig,Marcella Rietschel,Catherine Schaefer,Thomas Schulze,Jordan Smoller,Kari Stefansson,Henning Tiemeier,Rudolf Uher,Henry Völzke,Myrna Weissman,Thomas Werge,Ashley Winslow,Cathryn Lewis,Douglas Levinson,Gerome Breen,Anders Børglum,Patrick Sullivan,for Consortium,Ning Cai,Brittany Mitchell,Jun Liu,Huan Liu,Paul O’Reilly,Högni Óskarsson,Daniëlle Posthuma,Jorge Quiróz,Lei Shen,Engilbert Sigurðsson,Jan Smit,Kári Stéfansson,Eco Geus,Tõnu Esko,Paul Madden,Andrew McIntosh,Bertram Müller‐Myhsok,Silviu‐Alin Bacanu,Marie Bækvad‐Hansen,Jonas Bybjerg‐Grauholm,Toni‐Kim Clarke,Lucía Colodro‐Conde,Baptiste Couvy‐Duchesne,Neşe Direk,Valentina Escott‐Price,Michael O’Donovan,Jouke Hottenga,Anna Jansen,Zoltán Kutalik,Reedik Mägi,Francis McMahon
+246 authors
,Michel Nivard
Published
Jul 24, 2017
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Abstract

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=8.5×10 −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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