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

doi:10.1038/s41588-018-0090-3

Meta-Analysis

. 2018 May;50(5):668-681.

doi: 10.1038/s41588-018-0090-3. Epub 2018 Apr 26.

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

Naomi R Wray^#^{1

2}, Stephan Ripke^#^{3

4

5}, Manuel Mattheisen^#^{6

7

8

9}, Maciej Trzaskowski^#¹⁰, Enda M Byrne¹⁰, Abdel Abdellaoui¹¹, Mark J Adams¹², Esben Agerbo^{8

13

14}, Tracy M Air¹⁵, Till M F Andlauer^{16

17}, Silviu-Alin Bacanu¹⁸, Marie Bækvad-Hansen^{8

19}, Aartjan F T Beekman²⁰, Tim B Bigdeli^{18

21}, Elisabeth B Binder^{16

22}, Douglas R H Blackwood¹², Julien Bryois²³, Henriette N Buttenschøn^{7

8

24}, Jonas Bybjerg-Grauholm^{8

19}, Na Cai^{25

26}, Enrique Castelao²⁷, Jane Hvarregaard Christensen^{6

7

8}, Toni-Kim Clarke¹², Jonathan I R Coleman²⁸, Lucía Colodro-Conde²⁹, Baptiste Couvy-Duchesne^{30

31}, Nick Craddock³², Gregory E Crawford^{33

34}, Cheynna A Crowley³⁵, Hassan S Dashti^{3

36}, Gail Davies³⁷, Ian J Deary³⁷, Franziska Degenhardt^{38

39}, Eske M Derks²⁹, Nese Direk^{40

41}, Conor V Dolan¹¹, Erin C Dunn^{42

43

44}, Thalia C Eley²⁸, Nicholas Eriksson⁴⁵, Valentina Escott-Price⁴⁶, Farnush Hassan Farhadi Kiadeh⁴⁷, Hilary K Finucane^{48

49}, Andreas J Forstner^{38

39

50

51}, Josef Frank⁵², Héléna A Gaspar²⁸, Michael Gill⁵³, Paola Giusti-Rodríguez⁵⁴, Fernando S Goes⁵⁵, Scott D Gordon⁵⁶, Jakob Grove^{6

7

8

57}, Lynsey S Hall^{12

58}, Eilis Hannon⁵⁹, Christine Søholm Hansen^{8

19}, Thomas F Hansen^{60

61

62}, Stefan Herms^{38

39

51}, Ian B Hickie⁶³, Per Hoffmann^{38

39

51}, Georg Homuth⁶⁴, Carsten Horn⁶⁵, Jouke-Jan Hottenga¹¹, David M Hougaard^{8

19}, Ming Hu⁶⁶, Craig L Hyde⁶⁷, Marcus Ising⁶⁸, Rick Jansen²⁰, Fulai Jin^{69

70}, Eric Jorgenson⁷¹, James A Knowles⁷², Isaac S Kohane^{73

74

75}, Julia Kraft⁵, Warren W Kretzschmar⁷⁶, Jesper Krogh⁷⁷, Zoltán Kutalik^{78

79}, Jacqueline M Lane^{3

36

80}, Yihan Li⁷⁶, Yun Li^{35

54}, Penelope A Lind²⁹, Xiaoxiao Liu⁷⁰, Leina Lu⁷⁰, Donald J MacIntyre^{81

82}, Dean F MacKinnon⁵⁵, Robert M Maier³⁰, Wolfgang Maier⁸³, Jonathan Marchini⁸⁴, Hamdi Mbarek¹¹, Patrick McGrath⁸⁵, Peter McGuffin²⁸, Sarah E Medland²⁹, Divya Mehta^{30

86}, Christel M Middeldorp^{11

87

88}, Evelin Mihailov⁸⁹, Yuri Milaneschi²⁰, Lili Milani⁸⁹, Jonathan Mill⁵⁹, Francis M Mondimore⁵⁵, Grant W Montgomery¹⁰, Sara Mostafavi^{90

91}, Niamh Mullins²⁸, Matthias Nauck^{92

93}, Bernard Ng⁹¹, Michel G Nivard¹¹, Dale R Nyholt⁹⁴, Paul F O'Reilly²⁸, Hogni Oskarsson⁹⁵, Michael J Owen⁹⁶, Jodie N Painter²⁹, Carsten Bøcker Pedersen^{8

13

14}, Marianne Giørtz Pedersen^{8

13

14}, Roseann E Peterson^{18

97}, Erik Pettersson²³, Wouter J Peyrot²⁰, Giorgio Pistis²⁷, Danielle Posthuma^{98

99}, Shaun M Purcell¹⁰⁰, Jorge A Quiroz¹⁰¹, Per Qvist^{6

7

8}, John P Rice¹⁰², Brien P Riley¹⁸, Margarita Rivera^{28

103}, Saira Saeed Mirza⁴¹, Richa Saxena^{3

36

80}, Robert Schoevers¹⁰⁴, Eva C Schulte^{105

106}, Ling Shen⁷¹, Jianxin Shi¹⁰⁷, Stanley I Shyn¹⁰⁸, Engilbert Sigurdsson¹⁰⁹, Grant B C Sinnamon¹¹⁰, Johannes H Smit²⁰, Daniel J Smith¹¹¹, Hreinn Stefansson¹¹², Stacy Steinberg¹¹², Craig A Stockmeier¹¹³, Fabian Streit⁵², Jana Strohmaier⁵², Katherine E Tansey¹¹⁴, Henning Teismann¹¹⁵, Alexander Teumer¹¹⁶, Wesley Thompson^{8

61

117

118}, Pippa A Thomson¹¹⁹, Thorgeir E Thorgeirsson¹¹², Chao Tian⁴⁵, Matthew Traylor¹²⁰, Jens Treutlein⁵², Vassily Trubetskoy⁵, André G Uitterlinden¹²¹, Daniel Umbricht¹²², Sandra Van der Auwera¹²³, Albert M van Hemert¹²⁴, Alexander Viktorin²³, Peter M Visscher^{10

30}, Yunpeng Wang^{8

61

117}, Bradley T Webb¹²⁵, Shantel Marie Weinsheimer^{8

61}, Jürgen Wellmann¹¹⁵, Gonneke Willemsen¹¹, Stephanie H Witt⁵², Yang Wu¹⁰, Hualin S Xi¹²⁶, Jian Yang^{10

30}, Futao Zhang¹⁰; eQTLGen; 23andMe; Volker Arolt¹²⁷, Bernhard T Baune¹⁵, Klaus Berger¹¹⁵, Dorret I Boomsma¹¹, Sven Cichon^{38

51

128

129}, Udo Dannlowski¹²⁷, E C J de Geus^{11

130}, J Raymond DePaulo⁵⁵, Enrico Domenici¹³¹, Katharina Domschke¹³², Tõnu Esko^{3

89}, Hans J Grabe¹²³, Steven P Hamilton¹³³, Caroline Hayward¹³⁴, Andrew C Heath¹⁰², David A Hinds⁴⁵, Kenneth S Kendler¹⁸, Stefan Kloiber^{68

135

136}, Glyn Lewis¹³⁷, Qingqin S Li¹³⁸, Susanne Lucae⁶⁸, Pamela F A Madden¹⁰², Patrik K Magnusson²³, Nicholas G Martin⁵⁶, Andrew M McIntosh^{12

37}, Andres Metspalu^{89

139}, Ole Mors^{8

140}, Preben Bo Mortensen^{7

8

13

14}, Bertram Müller-Myhsok^{16

17

141}, Merete Nordentoft^{8

142}, Markus M Nöthen^{38

39}, Michael C O'Donovan⁹⁶, Sara A Paciga¹⁴³, Nancy L Pedersen²³, Brenda W J H Penninx²⁰, Roy H Perlis^{43

144}, David J Porteous¹¹⁹, James B Potash¹⁴⁵, Martin Preisig²⁷, Marcella Rietschel⁵², Catherine Schaefer⁷¹, Thomas G Schulze^{52

55

106

146

147}, Jordan W Smoller^{42

43

44}, Kari Stefansson^{112

148}, Henning Tiemeier^{41

149

150}, Rudolf Uher¹⁵¹, Henry Völzke¹¹⁶, Myrna M Weissman^{85

152}, Thomas Werge^{8

61

153}, Ashley R Winslow^{154

155}, Cathryn M Lewis^{28

156}, Douglas F Levinson¹⁵⁷, Gerome Breen^{28

158}, Anders D Børglum^{6

7

8}, Patrick F Sullivan^{159

160

161}; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Affiliations

¹ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. naomi.wray@uq.edu.au.
² Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia. naomi.wray@uq.edu.au.
³ Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
⁴ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁵ Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, Germany.
⁶ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁷ iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
⁸ iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
⁹ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
¹⁰ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
¹¹ Department of Biological Psychology and EMGO+ Institute for Health and Care Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹² Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
¹³ Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark.
¹⁴ National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
¹⁵ Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia.
¹⁶ Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
¹⁷ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
¹⁸ Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
¹⁹ Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
²⁰ Department of Psychiatry, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, The Netherlands.
²¹ Virginia Institute for Psychiatric and Behavior Genetics, Richmond, VA, USA.
²² Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
²³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁴ Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark.
²⁵ Statistical Genomics and Systems Genetics, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK.
²⁶ Human Genetics, Wellcome Trust Sanger Institute, Cambridge, UK.
²⁷ Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland.
²⁸ MRC Social Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
²⁹ Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
³⁰ Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
³¹ Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia.
³² Psychological Medicine, Cardiff University, Cardiff, UK.
³³ Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
³⁴ Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, USA.
³⁵ Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁶ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁷ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
³⁸ Institute of Human Genetics, University of Bonn, Bonn, Germany.
³⁹ Life & Brain Center, Department of Genomics, University of Bonn, Bonn, Germany.
⁴⁰ Psychiatry, Dokuz Eylul University School of Medicine, Izmir, Turkey.
⁴¹ Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
⁴² Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
⁴³ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁴⁴ Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, USA.
⁴⁵ Research, 23andMe, Inc., Mountain View, CA, USA.
⁴⁶ Neuroscience and Mental Health, Cardiff University, Cardiff, UK.
⁴⁷ Bioinformatics, University of British Columbia, Vancouver, British Columbia, Canada.
⁴⁸ Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
⁴⁹ Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵⁰ Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
⁵¹ Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
⁵² Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁵³ Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.
⁵⁴ Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵⁵ Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
⁵⁶ Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁵⁷ Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
⁵⁸ Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
⁵⁹ University of Exeter Medical School, Exeter, UK.
⁶⁰ Danish Headache Centre, Department of Neurology, Rigshospitalet, Glostrup, Denmark.
⁶¹ Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Capital Region of Denmark, Copenhagen, Denmark.
⁶² iPSYCH, Lundbeck Foundation Initiative for Psychiatric Research, Copenhagen, Denmark.
⁶³ Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
⁶⁴ Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
⁶⁵ Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd, Basel, Switzerland.
⁶⁶ Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA.
⁶⁷ Statistics, Pfizer Global Research and Development, Groton, CT, USA.
⁶⁸ Max Planck Institute of Psychiatry, Munich, Germany.
⁶⁹ Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
⁷⁰ Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
⁷¹ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
⁷² Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, USA.
⁷³ Informatics Program, Boston Children's Hospital, Boston, MA, USA.
⁷⁴ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁷⁵ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁷⁶ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁷⁷ Department of Endocrinology at Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark.
⁷⁸ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁷⁹ Institute of Social and Preventive Medicine (IUMSP), University Hospital of Lausanne, Lausanne, Switzerland.
⁸⁰ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁸¹ Mental Health, NHS 24, Glasgow, UK.
⁸² Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
⁸³ Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
⁸⁴ Statistics, University of Oxford, Oxford, UK.
⁸⁵ Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA.
⁸⁶ School of Psychology and Counseling, Queensland University of Technology, Brisbane, Queensland, Australia.
⁸⁷ Child and Youth Mental Health Service, Children's Health Queensland Hospital and Health Service, South Brisbane, Queensland, Australia.
⁸⁸ Child Health Research Centre, University of Queensland, Brisbane, Queensland, Australia.
⁸⁹ Estonian Genome Center, University of Tartu, Tartu, Estonia.
⁹⁰ Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
⁹¹ Statistics, University of British Columbia, Vancouver, British Columbia, Canada.
⁹² DZHK (German Centre for Cardiovascular Research), partner site Greifswald, University Medicine, University Medicine Greifswald, Greifswald, Germany.
⁹³ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
⁹⁴ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
⁹⁵ Humus, Reykjavik, Iceland.
⁹⁶ MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
⁹⁷ Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
⁹⁸ Complex Trait Genetics, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁹⁹ Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
¹⁰⁰ Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰¹ Solid Biosciences, Boston, MA, USA.
¹⁰² Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
¹⁰³ Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain.
¹⁰⁴ Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁰⁵ Department of Psychiatry and Psychotherapy, Medical Center of the University of Munich, Campus Innenstadt, Munich, Germany.
¹⁰⁶ Institute of Psychiatric Phenomics and Genomics (IPPG), Medical Center of the University of Munich, Campus Innenstadt, Munich, Germany.
¹⁰⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
¹⁰⁸ Behavioral Health Services, Kaiser Permanente Washington, Seattle, WA, USA.
¹⁰⁹ Faculty of Medicine, Department of Psychiatry, University of Iceland, Reykjavik, Iceland.
¹¹⁰ School of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.
¹¹¹ Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
¹¹² deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
¹¹³ Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA.
¹¹⁴ College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK.
¹¹⁵ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
¹¹⁶ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹¹⁷ KG Jebsen Centre for Psychosis Research, Norway Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹¹⁸ Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
¹¹⁹ Medical Genetics Section, CGEM, IGMM, University of Edinburgh, Edinburgh, UK.
¹²⁰ Clinical Neurosciences, University of Cambridge, Cambridge, UK.
¹²¹ Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
¹²² Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Medicine Area, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd, Basel, Switzerland.
¹²³ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
¹²⁴ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
¹²⁵ Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
¹²⁶ Computational Sciences Center of Emphasis, Pfizer Global Research and Development, Cambridge, MA, USA.
¹²⁷ Department of Psychiatry, University of Münster, Munster, Germany.
¹²⁸ Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.
¹²⁹ Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
¹³⁰ Amsterdam Public Health Institute, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
¹³¹ Centre for Integrative Biology, Università degli Studi di Trento, Trento, Italy.
¹³² Department of Psychiatry and Psychotherapy, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹³³ Psychiatry, Kaiser Permanente Northern California, San Francisco, CA, USA.
¹³⁴ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
¹³⁵ Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
¹³⁶ Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
¹³⁷ Division of Psychiatry, University College London, London, UK.
¹³⁸ Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, USA.
¹³⁹ Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
¹⁴⁰ Psychosis Research Unit, Aarhus University Hospital, Risskov, Aarhus, Denmark.
¹⁴¹ Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
¹⁴² Mental Health Center Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁴³ Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Groton, CT, USA.
¹⁴⁴ Psychiatry, Harvard Medical School, Boston, MA, USA.
¹⁴⁵ Psychiatry, University of Iowa, Iowa City, IA, USA.
¹⁴⁶ Human Genetics Branch, NIMH Division of Intramural Research Programs, Bethesda, MD, USA.
¹⁴⁷ Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
¹⁴⁸ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁴⁹ Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, The Netherlands.
¹⁵⁰ Psychiatry, Erasmus MC, Rotterdam, The Netherlands.
¹⁵¹ Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
¹⁵² Division of Epidemiology, New York State Psychiatric Institute, New York, NY, USA.
¹⁵³ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹⁵⁴ Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Cambridge, MA, USA.
¹⁵⁵ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵⁶ Department of Medical and Molecular Genetics, King's College London, London, UK.
¹⁵⁷ Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
¹⁵⁸ NIHR BRC for Mental Health, King's College London, London, UK.
¹⁵⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. pfsulliv@med.unc.edu.
¹⁶⁰ Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. pfsulliv@med.unc.edu.
¹⁶¹ Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. pfsulliv@med.unc.edu.

^# Contributed equally.

PMID: 29700475
PMCID: PMC5934326
DOI: 10.1038/s41588-018-0090-3

Meta-Analysis

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

Naomi R Wray et al. Nat Genet. 2018 May.

. 2018 May;50(5):668-681.

doi: 10.1038/s41588-018-0090-3. Epub 2018 Apr 26.

Authors

Affiliations

¹ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. naomi.wray@uq.edu.au.
² Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia. naomi.wray@uq.edu.au.
³ Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
⁴ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁵ Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, Germany.
⁶ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁷ iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
⁸ iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
⁹ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
¹⁰ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
¹¹ Department of Biological Psychology and EMGO+ Institute for Health and Care Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹² Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
¹³ Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark.
¹⁴ National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
¹⁵ Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia.
¹⁶ Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
¹⁷ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
¹⁸ Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
¹⁹ Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
²⁰ Department of Psychiatry, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, The Netherlands.
²¹ Virginia Institute for Psychiatric and Behavior Genetics, Richmond, VA, USA.
²² Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
²³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁴ Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark.
²⁵ Statistical Genomics and Systems Genetics, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK.
²⁶ Human Genetics, Wellcome Trust Sanger Institute, Cambridge, UK.
²⁷ Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland.
²⁸ MRC Social Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
²⁹ Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
³⁰ Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
³¹ Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia.
³² Psychological Medicine, Cardiff University, Cardiff, UK.
³³ Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
³⁴ Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, USA.
³⁵ Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁶ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁷ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
³⁸ Institute of Human Genetics, University of Bonn, Bonn, Germany.
³⁹ Life & Brain Center, Department of Genomics, University of Bonn, Bonn, Germany.
⁴⁰ Psychiatry, Dokuz Eylul University School of Medicine, Izmir, Turkey.
⁴¹ Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
⁴² Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
⁴³ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁴⁴ Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, USA.
⁴⁵ Research, 23andMe, Inc., Mountain View, CA, USA.
⁴⁶ Neuroscience and Mental Health, Cardiff University, Cardiff, UK.
⁴⁷ Bioinformatics, University of British Columbia, Vancouver, British Columbia, Canada.
⁴⁸ Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
⁴⁹ Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵⁰ Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
⁵¹ Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
⁵² Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁵³ Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.
⁵⁴ Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵⁵ Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
⁵⁶ Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁵⁷ Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
⁵⁸ Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
⁵⁹ University of Exeter Medical School, Exeter, UK.
⁶⁰ Danish Headache Centre, Department of Neurology, Rigshospitalet, Glostrup, Denmark.
⁶¹ Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Capital Region of Denmark, Copenhagen, Denmark.
⁶² iPSYCH, Lundbeck Foundation Initiative for Psychiatric Research, Copenhagen, Denmark.
⁶³ Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
⁶⁴ Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
⁶⁵ Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd, Basel, Switzerland.
⁶⁶ Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA.
⁶⁷ Statistics, Pfizer Global Research and Development, Groton, CT, USA.
⁶⁸ Max Planck Institute of Psychiatry, Munich, Germany.
⁶⁹ Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
⁷⁰ Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
⁷¹ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
⁷² Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, USA.
⁷³ Informatics Program, Boston Children's Hospital, Boston, MA, USA.
⁷⁴ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁷⁵ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁷⁶ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁷⁷ Department of Endocrinology at Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark.
⁷⁸ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁷⁹ Institute of Social and Preventive Medicine (IUMSP), University Hospital of Lausanne, Lausanne, Switzerland.
⁸⁰ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁸¹ Mental Health, NHS 24, Glasgow, UK.
⁸² Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
⁸³ Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
⁸⁴ Statistics, University of Oxford, Oxford, UK.
⁸⁵ Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA.
⁸⁶ School of Psychology and Counseling, Queensland University of Technology, Brisbane, Queensland, Australia.
⁸⁷ Child and Youth Mental Health Service, Children's Health Queensland Hospital and Health Service, South Brisbane, Queensland, Australia.
⁸⁸ Child Health Research Centre, University of Queensland, Brisbane, Queensland, Australia.
⁸⁹ Estonian Genome Center, University of Tartu, Tartu, Estonia.
⁹⁰ Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
⁹¹ Statistics, University of British Columbia, Vancouver, British Columbia, Canada.
⁹² DZHK (German Centre for Cardiovascular Research), partner site Greifswald, University Medicine, University Medicine Greifswald, Greifswald, Germany.
⁹³ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
⁹⁴ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
⁹⁵ Humus, Reykjavik, Iceland.
⁹⁶ MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
⁹⁷ Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
⁹⁸ Complex Trait Genetics, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁹⁹ Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
¹⁰⁰ Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰¹ Solid Biosciences, Boston, MA, USA.
¹⁰² Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
¹⁰³ Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain.
¹⁰⁴ Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁰⁵ Department of Psychiatry and Psychotherapy, Medical Center of the University of Munich, Campus Innenstadt, Munich, Germany.
¹⁰⁶ Institute of Psychiatric Phenomics and Genomics (IPPG), Medical Center of the University of Munich, Campus Innenstadt, Munich, Germany.
¹⁰⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
¹⁰⁸ Behavioral Health Services, Kaiser Permanente Washington, Seattle, WA, USA.
¹⁰⁹ Faculty of Medicine, Department of Psychiatry, University of Iceland, Reykjavik, Iceland.
¹¹⁰ School of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.
¹¹¹ Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
¹¹² deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
¹¹³ Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA.
¹¹⁴ College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK.
¹¹⁵ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
¹¹⁶ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹¹⁷ KG Jebsen Centre for Psychosis Research, Norway Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹¹⁸ Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
¹¹⁹ Medical Genetics Section, CGEM, IGMM, University of Edinburgh, Edinburgh, UK.
¹²⁰ Clinical Neurosciences, University of Cambridge, Cambridge, UK.
¹²¹ Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
¹²² Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Medicine Area, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd, Basel, Switzerland.
¹²³ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
¹²⁴ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
¹²⁵ Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
¹²⁶ Computational Sciences Center of Emphasis, Pfizer Global Research and Development, Cambridge, MA, USA.
¹²⁷ Department of Psychiatry, University of Münster, Munster, Germany.
¹²⁸ Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.
¹²⁹ Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
¹³⁰ Amsterdam Public Health Institute, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
¹³¹ Centre for Integrative Biology, Università degli Studi di Trento, Trento, Italy.
¹³² Department of Psychiatry and Psychotherapy, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹³³ Psychiatry, Kaiser Permanente Northern California, San Francisco, CA, USA.
¹³⁴ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
¹³⁵ Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
¹³⁶ Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
¹³⁷ Division of Psychiatry, University College London, London, UK.
¹³⁸ Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, USA.
¹³⁹ Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
¹⁴⁰ Psychosis Research Unit, Aarhus University Hospital, Risskov, Aarhus, Denmark.
¹⁴¹ Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
¹⁴² Mental Health Center Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁴³ Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Groton, CT, USA.
¹⁴⁴ Psychiatry, Harvard Medical School, Boston, MA, USA.
¹⁴⁵ Psychiatry, University of Iowa, Iowa City, IA, USA.
¹⁴⁶ Human Genetics Branch, NIMH Division of Intramural Research Programs, Bethesda, MD, USA.
¹⁴⁷ Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
¹⁴⁸ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁴⁹ Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, The Netherlands.
¹⁵⁰ Psychiatry, Erasmus MC, Rotterdam, The Netherlands.
¹⁵¹ Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
¹⁵² Division of Epidemiology, New York State Psychiatric Institute, New York, NY, USA.
¹⁵³ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹⁵⁴ Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Cambridge, MA, USA.
¹⁵⁵ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵⁶ Department of Medical and Molecular Genetics, King's College London, London, UK.
¹⁵⁷ Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
¹⁵⁸ NIHR BRC for Mental Health, King's College London, London, UK.
¹⁵⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. pfsulliv@med.unc.edu.
¹⁶⁰ Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. pfsulliv@med.unc.edu.
¹⁶¹ Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. pfsulliv@med.unc.edu.

^# Contributed equally.

PMID: 29700475
PMCID: PMC5934326
DOI: 10.1038/s41588-018-0090-3

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.

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Conflict of interest statement

Competing Financial Interests

Aartjan TF Beekman: Speakers bureaus of Lundbeck and GlaxoSmithKline. Greg Crawford: Co-founder of Element Genomics. Enrico Domenici: Employee of Hoffmann-La Roche at the time this study was conducted, consultant to Roche and Pierre-Fabre. Nicholas Eriksson: Employed by 23andMe, Inc. and owns stock in 23andMe, Inc. David Hinds: Employee of and own stock options in 23andMe, Inc. Sara Paciga: Employee of Pfizer, Inc. Craig L Hyde: Employee of Pfizer, Inc. Ashley R Winslow: Former employee and stockholder of Pfizer, Inc. Jorge A Quiroz: Employee of Hoffmann-La Roche at the time this study was conducted. Hreinn Stefansson: Employee of deCODE Genetics/AMGEN. Kari Stefansson: Employee of deCODE Genetics/AMGEN. Stacy Steinberg: Employee of deCODE Genetics/AMGEN. Patrick F Sullivan: Scientific advisory board for Pfizer Inc and an advisory committee for Lundbeck. Thorgeir E Thorgeirsson: Employee of deCODE Genetics/AMGEN. Chao Tian: Employee of and own stock options in 23andMe, Inc.

Figures

**Fig. 1. Results of GWA meta-analysis of seven cohorts for major depression**
(a) Relation between adding cohorts and number of genome-wide significant genomic regions (before the rigorous vetting used to define the final 44 regions). Beginning with the largest cohort (#1 on the x-axis), added the next largest cohort (#2) until all cohorts were included (#7). The number next to each point shows the total effective sample size equivalent to sample size where the numbers of cases and controls are equal. (b) Association test quantile-quantile plot showing a marked departure from a null model of no associations (y-axis truncated 10⁻¹²). (c) Manhattan plot with x-axis showing genomic position (chr1-chr22 plus chrX), and the y-axis showing statistical significance as –log₁₀(P) t-statistic; threshold for significance accounting for multiple testing shown by horizontal line. Association test from meta-analysis of 135,458 major depression cases and 344,901 controls. The red line shows the genome-wide significance threshold (P=5×10⁻⁸).

**Fig. 2. Genetic risk score (GRS) prediction analyses into PGC29 MDD target samples**
(a) Variance explained (liability scale) based on different discovery samples for three target samples: PGC29 (16,823 cases, 25,632 controls), iPSYCH (a nationally representative sample of 18,629 cases and 17,841 controls,) and a clinical cohort from Münster not included in the GWA analysis (845 MDD inpatient cases, 834 controls). PGC29-LOO: Target sample is one of the PGC29 samples, with discovery sample the remaining 28 PGC29 samples, hence, leave-one-out. (b) Odds ratios of major depression per GRS decile relative to the first decile for iPSYCH and PGC29 target samples. (c) Odds ratios of major depression in GRS standard deviation (SD): 3,950 early onset vs 3,950 late onset cases earlier age at onset; 4,958 severe vs 3,976 moderate cases defined by count of endorsed MDD symptom criteria; 5,574 cases recurrent MDD vs 12,968 single episode cases; severity defined as chronic/unremitting MDD 610 “Stage IV” cases vs 499 “Stage II” or 332 first-episode MDD used the NESDA sample from PGC29. Error bars represent 95% confidence intervals. Logistic regression association test p-values in the target sample for GRS generated from SNPs with p-value < 0.05 in the discovery sample.

**Fig. 3. Comparisons of the major depression GWA meta-analysis**
(a) Enrichment in bulk tissue mRNA-seq from GTEx; t-statistic, sample sizes in GTEx range from N=75–564. Threshold for significance accounting for multiple testing shown by vertical line. (b) Major depression results and enrichment in three major brain cell types; t-statistic; threshold for significance accounting for multiple testing shown by horizontal line. Sample sizes vary as these data are aggregated from many different sources. (c) Partitioned LDSC to evaluate enrichment of the major depression GWA findings in over 50 functional genomic annotations (Supplementary Table 8); enrichment statistic; threshold for significance accounting for multiple testing given by horizontal dashed line. Sample sizes vary as these data are aggregated from many different sources.

**Fig. 4**
Generative topographic mapping of the 19 significant pathway results. The average position of each pathway on the map is represented by a point. The map is colored by the –log₁₀(P) obtained using MAGMA. The X and Y coordinates result from a kernel generative topographic mapping algorithm (GTM) that reduces high dimensional gene sets to a two-dimensional scatterplot by accounting for gene overlap between gene sets. Each point represents a gene set. Nearby points are more similar in gene overlap than more distant points. The color surrounding each point (gene set) indicates significance per the scale on the right. The significant pathways (Supplementary Table 11) fall into nine main clusters as described in the text.

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References

1. Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Annu Rev Public Health. 2013;34:119–38. - PMC - PubMed
1. Judd LL. The clinical course of unipolar major depressive disorders. Archives of general psychiatry. 1997;54:989–91. - PubMed
1. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006;367:1747–57. - PubMed
1. Wittchen HU, et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2011;21:655–79. - PubMed
1. Ferrari AJ, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med. 2013;10:e1001547. - PMC - PubMed

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[1] Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Annu Rev Public Health. 2013;34:119–38. - PMC - PubMed

[2] Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Annu Rev Public Health. 2013;34:119–38. - PMC - PubMed

[3] Judd LL. The clinical course of unipolar major depressive disorders. Archives of general psychiatry. 1997;54:989–91. - PubMed

[4] Judd LL. The clinical course of unipolar major depressive disorders. Archives of general psychiatry. 1997;54:989–91. - PubMed

[5] Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006;367:1747–57. - PubMed

[6] Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006;367:1747–57. - PubMed

[7] Wittchen HU, et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2011;21:655–79. - PubMed

[8] Wittchen HU, et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2011;21:655–79. - PubMed

[9] Ferrari AJ, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med. 2013;10:e1001547. - PMC - PubMed

[10] Ferrari AJ, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med. 2013;10:e1001547. - PMC - PubMed

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

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

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