Abstract
Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.
Original language | English |
---|---|
Pages (from-to) | 668-681 |
Number of pages | 14 |
Journal | Nature Genetics |
Volume | 50 |
Issue number | 5 |
DOIs | |
State | Published - May 1 2018 |
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In: Nature Genetics, Vol. 50, No. 5, 01.05.2018, p. 668-681.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression
AU - Wray, Naomi R.
AU - Ripke, Stephan
AU - Mattheisen, Manuel
AU - Trzaskowski, MacIej
AU - Byrne, Enda M.
AU - Abdellaoui, Abdel
AU - Adams, Mark J.
AU - Agerbo, Esben
AU - Air, Tracy M.
AU - Andlauer, Till M.F.
AU - Bacanu, Silviu Alin
AU - Bækvad-Hansen, Marie
AU - Beekman, Aartjan F.T.
AU - Bigdeli, Tim B.
AU - Binder, Elisabeth B.
AU - Blackwood, Douglas R.H.
AU - Bryois, Julien
AU - Buttenschøn, Henriette N.
AU - Bybjerg-Grauholm, Jonas
AU - Cai, Na
AU - Castelao, Enrique
AU - Christensen, Jane Hvarregaard
AU - Clarke, Toni Kim
AU - Coleman, Jonathan I.R.
AU - Colodro-Conde, Lucía
AU - Couvy-Duchesne, Baptiste
AU - Craddock, Nick
AU - Crawford, Gregory E.
AU - Crowley, Cheynna A.
AU - Dashti, Hassan S.
AU - Davies, Gail
AU - Deary, Ian J.
AU - Degenhardt, Franziska
AU - Derks, Eske M.
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AU - Dolan, Conor V.
AU - Dunn, Erin C.
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AU - Eriksson, Nicholas
AU - Escott-Price, Valentina
AU - Kiadeh, Farnush Hassan Farhadi
AU - Finucane, Hilary K.
AU - Forstner, Andreas J.
AU - Frank, Josef
AU - Gaspar, Héléna A.
AU - Gill, Michael
AU - Giusti-Rodríguez, Paola
AU - Goes, Fernando S.
AU - Gordon, Scott D.
AU - Grove, Jakob
AU - Hall, Lynsey S.
AU - Hannon, Eilis
AU - Hansen, Christine Søholm
AU - Hansen, Thomas F.
AU - Herms, Stefan
AU - Hickie, Ian B.
AU - Hoffmann, Per
AU - Homuth, Georg
AU - Horn, Carsten
AU - Hottenga, Jouke Jan
AU - Hougaard, David M.
AU - Hu, Ming
AU - Hyde, Craig L.
AU - Ising, Marcus
AU - Jansen, Rick
AU - Jin, Fulai
AU - Jorgenson, Eric
AU - Knowles, James A.
AU - Kohane, Isaac S.
AU - Kraft, Julia
AU - Kretzschmar, Warren W.
AU - Krogh, Jesper
AU - Kutalik, Zoltán
AU - Lane, Jacqueline M.
AU - Li, Yihan
AU - Li, Yun
AU - Lind, Penelope A.
AU - Liu, Xiaoxiao
AU - Lu, Leina
AU - MacIntyre, Donald J.
AU - MacKinnon, Dean F.
AU - Maier, Robert M.
AU - Maier, Wolfgang
AU - Marchini, Jonathan
AU - Mbarek, Hamdi
AU - McGrath, Patrick
AU - McGuffin, Peter
AU - Medland, Sarah E.
AU - Mehta, DIvya
AU - Middeldorp, Christel M.
AU - Mihailov, Evelin
AU - Milaneschi, Yuri
AU - Milani, Lili
AU - Mill, Jonathan
AU - Mondimore, Francis M.
AU - Montgomery, Grant W.
AU - Mostafavi, Sara
AU - Mullins, Niamh
AU - Nauck, Matthias
AU - Ng, Bernard
AU - Nivard, Michel G.
AU - Nyholt, Dale R.
AU - O'Reilly, Paul F.
AU - Oskarsson, Hogni
AU - Owen, Michael J.
AU - Painter, Jodie N.
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AU - Pedersen, Marianne Giørtz
AU - Peterson, Roseann E.
AU - Pettersson, Erik
AU - Peyrot, Wouter J.
AU - Pistis, Giorgio
AU - Posthuma, Danielle
AU - Purcell, Shaun M.
AU - Quiroz, Jorge A.
AU - Qvist, Per
AU - Rice, John P.
AU - Riley, Brien P.
AU - Rivera, Margarita
AU - Saeed Mirza, Saira
AU - Saxena, Richa
AU - Schoevers, Robert
AU - Schulte, Eva C.
AU - Shen, Ling
AU - Shi, Jianxin
AU - Shyn, Stanley I.
AU - Sigurdsson, Engilbert
AU - Sinnamon, Grant B.C.
AU - Smit, Johannes H.
AU - Smith, Daniel J.
AU - Stefansson, Hreinn
AU - Steinberg, Stacy
AU - Stockmeier, Craig A.
AU - Streit, Fabian
AU - Strohmaier, Jana
AU - Tansey, Katherine E.
AU - Teismann, Henning
AU - Teumer, Alexander
AU - Thompson, Wesley
AU - Thomson, Pippa A.
AU - Thorgeirsson, Thorgeir E.
AU - Tian, Chao
AU - Traylor, Matthew
AU - Treutlein, Jens
AU - Trubetskoy, Vassily
AU - Uitterlinden, André G.
AU - Umbricht, Daniel
AU - Van Der Auwera, Sandra
AU - Van Hemert, Albert M.
AU - Viktorin, Alexander
AU - Visscher, Peter M.
AU - Wang, Yunpeng
AU - Webb, Bradley T.
AU - Weinsheimer, Shantel Marie
AU - Wellmann, Jürgen
AU - Willemsen, Gonneke
AU - Witt, Stephanie H.
AU - Wu, Yang
AU - Xi, Hualin S.
AU - Yang, Jian
AU - Zhang, Futao
AU - Arolt, Volker
AU - Baune, Bernhard T.
AU - Berger, Klaus
AU - Boomsma, Dorret I.
AU - Cichon, Sven
AU - Dannlowski, Udo
AU - De Geus, E. C.J.
AU - Depaulo, J. Raymond
AU - Domenici, Enrico
AU - Domschke, Katharina
AU - Esko, Tõnu
AU - Grabe, Hans J.
AU - Hamilton, Steven P.
AU - Hayward, Caroline
AU - Heath, Andrew C.
AU - Hinds, David A.
AU - Kendler, Kenneth S.
AU - Kloiber, Stefan
AU - Lewis, Glyn
AU - Li, Qingqin S.
AU - Lucae, Susanne
AU - Madden, Pamela F.A.
AU - Magnusson, Patrik K.
AU - Martin, Nicholas G.
AU - McIntosh, Andrew M.
AU - Metspalu, Andres
AU - Mors, Ole
AU - Mortensen, Preben Bo
AU - Müller-Myhsok, Bertram
AU - Nordentoft, Merete
AU - Nöthen, Markus M.
AU - O'Donovan, Michael C.
AU - Paciga, Sara A.
AU - Pedersen, Nancy L.
AU - Penninx, Brenda W.J.H.
AU - Perlis, Roy H.
AU - Porteous, David J.
AU - Potash, James B.
AU - Preisig, Martin
AU - Rietschel, Marcella
AU - Schaefer, Catherine
AU - Schulze, Thomas G.
AU - Smoller, Jordan W.
AU - Stefansson, Kari
AU - Tiemeier, Henning
AU - Uher, Rudolf
AU - Völzke, Henry
AU - Weissman, Myrna M.
AU - Werge, Thomas
AU - Winslow, Ashley R.
AU - Lewis, Cathryn M.
AU - Levinson, Douglas F.
AU - Breen, Gerome
AU - Børglum, Anders D.
AU - Sullivan, Patrick F.
N1 - Funding Information: Full acknowledgments are in the Supplementary Note. We are deeply indebted to the investigators who comprise the PGC, and to the hundreds of thousands of subjects who have shared their life experiences with PGC investigators. A full list of funding is in the Supplementary Note. Major funding for the PGC is from the US National Institutes of Health (U01 MH109528 and U01 MH109532). Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org/) hosted by SURFsara. The iPSYCH team acknowledges funding from the Lundbeck Foundation (grants R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, the European Research Council (project 294838), the Novo Nordisk Foundation for supporting the Danish National Biobank resource, and Aarhus and Copenhagen Universities and University Hospitals, including support to the iSEQ Center, the GenomeDK HPC facility, and the CIRRAU Center. This research has been conducted using the UK Biobank Resource (see URLs), including applications 4844 and 6818. Finally, we thank the members of the eQTLGen Consortium for allowing us to use their very large eQTL database ahead of publication. Its members are listed in Supplementary Table 14. Funding Information: Some data used in this study were obtained from dbGaP (see URLs). dbGaP accession phs000021: funding support for the Genome-Wide Association of Schizophrenia Study was provided by the National Institute of Mental Health (R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289, U01 MH46318, U01 MH79469, and U01 MH79470), and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). Samples and associated phenotype data for the Genome-Wide Association of Schizophrenia Study were provided by the Molecular Genetics of Schizophrenia Collaboration (principal investigator P. V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, IL, USA). dbGaP accession phs000196: this work used in part data from the NINDS dbGaP database from the CIDR:NGRC PARKINSON’S DISEASE STUDY. dbGaP accession phs000187: High-Density SNP Association Analysis of Melanoma: Case–Control and Outcomes Investigation. Research support to collect data and develop an application to support this project was provided by P50 CA093459, P50 CA097007, R01 ES011740, and R01 CA133996 from the NIH. Publisher Copyright: © 2018 The Author(s).
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.
AB - Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.
UR - http://www.scopus.com/inward/record.url?scp=85046022254&partnerID=8YFLogxK
U2 - 10.1038/s41588-018-0090-3
DO - 10.1038/s41588-018-0090-3
M3 - Article
C2 - 29700475
AN - SCOPUS:85046022254
SN - 1061-4036
VL - 50
SP - 668
EP - 681
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -