Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depressive disorder
Authors: Wray Naomi R , Ripke Stephan , Mattheisen Manuel , Trzaskowski Maciej , Byrne Enda M , Abdellaoui Abdel , Adams Mark J , 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 , Blackwood Douglas H R , Bryois Julien , Buttenschøn Henriette N , Bybjerg-Grauholm Jonas , Cai Na , Castelao Enrique , Christensen Jane Hvarregaard , Clarke Toni-Kim , Coleman Jonathan R I , Colodro-Conde Lucía , Couvy-Duchesne Baptiste , Craddock Nick , Crawford Gregory E , Crowley Cheynna A , Dashti Hassan S , Davies Gail , Deary Ian J , Degenhardt Franziska , Derks Eske M , Direk Nese , Dolan Conor V , Dunn Erin C , Eley Thalia C , Eriksson Nicholas , Escott-Price Valentina , Hassan Kiadeh Farnush Farhadi , Finucane Hilary K , Forstner Andreas J , Frank Josef , Gaspar Héléna A , Gill Michael , Giusti-Rorínguez Paola , 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 , Hu Ming , Hyde Craig L , Ising Marcus , Jansen Rick , Jin Fulai , Jorgenson Eric , Knowles James A , Kohane Isaac S , Kraft Julia , Kretzschmar Warren W. , Krogh Jesper , Kutalik Zoltan , Lane Jacqueline M , Li Yihan , Li Yun , Lind Penelope A , Liu Xiaoxiao , Lu Leina , 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 , Bøcker Carsten , Pedersen Marianne Giørtz , Peterson Roseann E. , Pettersson Erik , Peyrot Wouter J , Pistis Giorgio , Posthuma Danielle , Purcell Shaun M , Quiroz Jorge A , Qvist Per , Rice John P , Riley Brien P. , Rivera Margarita , Mirza Saira Saeed , Saxena Richa , 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 , Stockmeier Craig A , Streit Fabian , Strohmaier Jana , Tansey Katherine E , Teismann Henning , Teumer Alexander , Thompson Wesley , Thomson Pippa a , Thorgeirsson Thorgeir E , Tian Chao , Traylor Matthew , Treutlein Jens , Trubetskoy Vassily , Uitterlinden André G , Umbricht Daniel , Auwera Sandra Van der , Hemert Albert M van , 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 ,   eQTLGen Consortium,   23andMe Research Team, Arolt Volker , Baune Bernhard T , Berger Klaus , Boomsma Dorret I , Cichon Sven , Dannlowski udo , de Geus EJC , DePaulo J Raymond , Domenici Enrico , Domschke Katharina , Esko Tönu , Grabe Hans J , Hamilton Steven P , Hayward Caroline , Heath Andrew C , Hinds David A , Kendler Kenneth S , Kloiber Stefan , Lewis Glyn , Li Qingqin S , Lucae Susanne , Madden Pamela AF , Magnusson Patrik K , Martin Nicholas G , McIntosh Andrew M , 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 WJH , 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 , Winslow Ashley R , Lewis Cathryn M , Levinson Douglas F , Breen Gerome , Børglum Anders D , Sullivan Patrick F ,   for the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
Published: July 2017

Major depressive disorder (MDD) is a notably complex illness with a lifetime prevalence of 14%.1It is often chronic or recurrent and is thus accompanied by considerable morbidity, excess mortality, substantial costs, and heightened risk of suicide.2-7MDD is a major cause of disability worldwide.8We 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.