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

Naomi R. Wray; Stephan Ripke; Manuel Mattheisen; MacIej Trzaskowski; Enda M. Byrne; Abdel Abdellaoui; Mark J. Adams; Esben Agerbo; Tracy M. Air; Till M.F. Andlauer; Silviu Alin Bacanu; Marie Bækvad-Hansen; Aartjan F.T. Beekman; Tim B. Bigdeli; Elisabeth B. Binder; Douglas R.H. Blackwood; Julien Bryois; Henriette N. Buttenschøn; Jonas Bybjerg-Grauholm; Na Cai; Enrique Castelao; Jane Hvarregaard Christensen; Toni Kim Clarke; Jonathan I.R. 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 Hassan Farhadi Kiadeh; Hilary K. Finucane; Andreas J. Forstner; Josef Frank; Héléna A. Gaspar; Michael Gill; Paola Giusti-Rodríguez; Fernando S. Goes; Scott D. Gordon; Jakob Grove; Lynsey S. Hall; Eilis Hannon; 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; Zoltán 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; Jonathan Mill; 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 Pedersen; 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 B.C. 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; Volker Arolt; Bernhard T. Baune; Klaus Berger; Dorret I. Boomsma; Sven Cichon; Udo Dannlowski; E. C.J. De Geus; J. Raymond Depaulo; Enrico Domenici; Katharina Domschke; Tõnu 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 F.A. 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

doi:10.1038/s41588-018-0090-3

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

Naomi R. Wray, Stephan Ripke, Manuel Mattheisen, MacIej Trzaskowski, Enda M. Byrne, Abdel Abdellaoui, Mark J. Adams, Esben Agerbo, Tracy M. Air, Till M.F. Andlauer, Silviu Alin Bacanu, Marie Bækvad-Hansen, Aartjan F.T. Beekman, Tim B. Bigdeli, Elisabeth B. Binder, Douglas R.H. Blackwood, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na CaiEnrique Castelao, Jane Hvarregaard Christensen, Toni Kim Clarke, Jonathan I.R. 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 Hassan Farhadi Kiadeh, Hilary K. Finucane, Andreas J. Forstner, Josef Frank, Héléna A. Gaspar, Michael Gill, Paola Giusti-Rodríguez, Fernando S. Goes, Scott D. Gordon, Jakob Grove, Lynsey S. Hall, Eilis Hannon, 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, Zoltán 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, Jonathan Mill, 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 Pedersen, 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 B.C. 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, Volker Arolt, Bernhard T. Baune, Klaus Berger, Dorret I. Boomsma, Sven Cichon, Udo Dannlowski, E. C.J. De Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Tõnu 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 F.A. 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

Research output: Contribution to journal › Article › peer-review

1281 Scopus citations

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	https://doi.org/10.1038/s41588-018-0090-3
State	Published - May 1 2018

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10.1038/s41588-018-0090-3

Cite this

Wray, N. R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E. M., Abdellaoui, A., Adams, M. J., Agerbo, E., Air, T. M., Andlauer, T. M. F., Bacanu, S. A., Bækvad-Hansen, M., Beekman, A. F. T., Bigdeli, T. B., Binder, E. B., Blackwood, D. R. H., Bryois, J., Buttenschøn, H. N., Bybjerg-Grauholm, J., ... Sullivan, P. F. (2018). Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nature Genetics, 50(5), 668-681. https://doi.org/10.1038/s41588-018-0090-3

@article{a9622b57a7fa4984932f9085bc7cd8e6,

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

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.",

author = "Wray, {Naomi R.} and Stephan Ripke and Manuel Mattheisen and MacIej Trzaskowski and Byrne, {Enda M.} and Abdel Abdellaoui and Adams, {Mark J.} and Esben Agerbo and Air, {Tracy M.} and Andlauer, {Till M.F.} and Bacanu, {Silviu Alin} and Marie B{\ae}kvad-Hansen and Beekman, {Aartjan F.T.} and Bigdeli, {Tim B.} and Binder, {Elisabeth B.} and Blackwood, {Douglas R.H.} and Julien Bryois and Buttensch{\o}n, {Henriette N.} and Jonas Bybjerg-Grauholm and Na Cai and Enrique Castelao and Christensen, {Jane Hvarregaard} and Clarke, {Toni Kim} and Coleman, {Jonathan I.R.} and Luc{\'i}a Colodro-Conde and Baptiste Couvy-Duchesne and Nick Craddock and Crawford, {Gregory E.} and Crowley, {Cheynna A.} and Dashti, {Hassan S.} and Gail Davies and Deary, {Ian J.} and Franziska Degenhardt and Derks, {Eske M.} and Nese DIrek and Dolan, {Conor V.} and Dunn, {Erin C.} and Eley, {Thalia C.} and Nicholas Eriksson and Valentina Escott-Price and Kiadeh, {Farnush Hassan Farhadi} and Finucane, {Hilary K.} and Forstner, {Andreas J.} and Josef Frank and Gaspar, {H{\'e}l{\'e}na A.} and Michael Gill and Paola Giusti-Rodr{\'i}guez and Goes, {Fernando S.} and Gordon, {Scott D.} and Jakob Grove and Hall, {Lynsey S.} and Eilis Hannon and Hansen, {Christine S{\o}holm} and Hansen, {Thomas F.} and Stefan Herms and Hickie, {Ian B.} and Per Hoffmann and Georg Homuth and Carsten Horn and Hottenga, {Jouke Jan} and Hougaard, {David M.} and Ming Hu and Hyde, {Craig L.} and Marcus Ising and Rick Jansen and Fulai Jin and Eric Jorgenson and Knowles, {James A.} and Kohane, {Isaac S.} and Julia Kraft and Kretzschmar, {Warren W.} and Jesper Krogh and Zolt{\'a}n Kutalik and Lane, {Jacqueline M.} and Yihan Li and Yun Li and Lind, {Penelope A.} and Xiaoxiao Liu and Leina Lu and MacIntyre, {Donald J.} and MacKinnon, {Dean F.} and Maier, {Robert M.} and Wolfgang Maier and Jonathan Marchini and Hamdi Mbarek and Patrick McGrath and Peter McGuffin and Medland, {Sarah E.} and DIvya Mehta and Middeldorp, {Christel M.} and Evelin Mihailov and Yuri Milaneschi and Lili Milani and Jonathan Mill and Mondimore, {Francis M.} and Montgomery, {Grant W.} and Sara Mostafavi and Niamh Mullins and Matthias Nauck and Bernard Ng and Nivard, {Michel G.} and Nyholt, {Dale R.} and O'Reilly, {Paul F.} and Hogni Oskarsson and Owen, {Michael J.} and Painter, {Jodie N.} and Pedersen, {Carsten B{\o}cker} and Pedersen, {Marianne Gi{\o}rtz} and Peterson, {Roseann E.} and Erik Pettersson and Peyrot, {Wouter J.} and Giorgio Pistis and Danielle Posthuma and Purcell, {Shaun M.} and Quiroz, {Jorge A.} and Per Qvist and Rice, {John P.} and Riley, {Brien P.} and Margarita Rivera and {Saeed Mirza}, Saira and Richa Saxena and Robert Schoevers and Schulte, {Eva C.} and Ling Shen and Jianxin Shi and Shyn, {Stanley I.} and Engilbert Sigurdsson and Sinnamon, {Grant B.C.} and Smit, {Johannes H.} and Smith, {Daniel J.} and Hreinn Stefansson and Stacy Steinberg and Stockmeier, {Craig A.} and Fabian Streit and Jana Strohmaier and Tansey, {Katherine E.} and Henning Teismann and Alexander Teumer and Wesley Thompson and Thomson, {Pippa A.} and Thorgeirsson, {Thorgeir E.} and Chao Tian and Matthew Traylor and Jens Treutlein and Vassily Trubetskoy and Uitterlinden, {Andr{\'e} G.} and Daniel Umbricht and {Van Der Auwera}, Sandra and {Van Hemert}, {Albert M.} and Alexander Viktorin and Visscher, {Peter M.} and Yunpeng Wang and Webb, {Bradley T.} and Weinsheimer, {Shantel Marie} and J{\"u}rgen Wellmann and Gonneke Willemsen and Witt, {Stephanie H.} and Yang Wu and Xi, {Hualin S.} and Jian Yang and Futao Zhang and Volker Arolt and Baune, {Bernhard T.} and Klaus Berger and Boomsma, {Dorret I.} and Sven Cichon and Udo Dannlowski and {De Geus}, {E. C.J.} and Depaulo, {J. Raymond} and Enrico Domenici and Katharina Domschke and T{\~o}nu Esko and Grabe, {Hans J.} and Hamilton, {Steven P.} and Caroline Hayward and Heath, {Andrew C.} and Hinds, {David A.} and Kendler, {Kenneth S.} and Stefan Kloiber and Glyn Lewis and Li, {Qingqin S.} and Susanne Lucae and Madden, {Pamela F.A.} and Magnusson, {Patrik K.} and Martin, {Nicholas G.} and McIntosh, {Andrew M.} and Andres Metspalu and Ole Mors and Mortensen, {Preben Bo} and Bertram M{\"u}ller-Myhsok and Merete Nordentoft and N{\"o}then, {Markus M.} and O'Donovan, {Michael C.} and Paciga, {Sara A.} and Pedersen, {Nancy L.} and Penninx, {Brenda W.J.H.} and Perlis, {Roy H.} and Porteous, {David J.} and Potash, {James B.} and Martin Preisig and Marcella Rietschel and Catherine Schaefer and Schulze, {Thomas G.} and Smoller, {Jordan W.} and Kari Stefansson and Henning Tiemeier and Rudolf Uher and Henry V{\"o}lzke and Weissman, {Myrna M.} and Thomas Werge and Winslow, {Ashley R.} and Lewis, {Cathryn M.} and Levinson, {Douglas F.} and Gerome Breen and B{\o}rglum, {Anders D.} and Sullivan, {Patrick F.}",

note = "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{\textquoteright}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: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = may,

day = "1",

doi = "10.1038/s41588-018-0090-3",

language = "English",

volume = "50",

pages = "668--681",

journal = "Nature Genetics",

issn = "1061-4036",

number = "5",

}

Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TMF, Bacanu, SA, Bækvad-Hansen, M, Beekman, AFT, Bigdeli, TB, Binder, EB, Blackwood, DRH, Bryois, J, Buttenschøn, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, TK, Coleman, JIR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Crowley, CA, Dashti, HS, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, DIrek, N, Dolan, CV, Dunn, EC, Eley, TC, Eriksson, N, Escott-Price, V, Kiadeh, FHF, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Giusti-Rodríguez, P, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hannon, E, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, JJ, Hougaard, DM, Hu, M, Hyde, CL, Ising, M, Jansen, R, Jin, F, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Lane, JM, Li, Y, Li, Y, Lind, PA, Liu, X, Lu, L, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, DI, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mill, J, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Purcell, SM, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Saeed Mirza, S, Saxena, R, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GBC, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Stockmeier, CA, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Tian, C, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van Der Auwera, S, Van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, De Geus, ECJ, Depaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Hinds, DA, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PFA, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Müller-Myhsok, B, Nordentoft, M, Nöthen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Völzke, H, Weissman, MM, Werge, T, Winslow, AR, Lewis, CM, Levinson, DF, Breen, G, Børglum, AD & Sullivan, PF 2018, 'Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression', Nature Genetics, vol. 50, no. 5, pp. 668-681. https://doi.org/10.1038/s41588-018-0090-3

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.

AU - DIrek, Nese

AU - Dolan, Conor V.

AU - Dunn, Erin C.

AU - Eley, Thalia C.

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

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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 -

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

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