Format

Send to

Choose Destination
Nat Genet. 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.

Wray NR1,2, Ripke S3,4,5, Mattheisen M6,7,8,9, Trzaskowski M10, Byrne EM10, Abdellaoui A11, Adams MJ12, Agerbo E8,13,14, Air TM15, Andlauer TMF16,17, Bacanu SA18, Bækvad-Hansen M8,19, Beekman AFT20, Bigdeli TB18,21, Binder EB16,22, Blackwood DRH12, Bryois J23, Buttenschøn HN7,8,24, Bybjerg-Grauholm J8,19, Cai N25,26, Castelao E27, Christensen JH6,7,8, Clarke TK12, Coleman JIR28, Colodro-Conde L29, Couvy-Duchesne B30,31, Craddock N32, Crawford GE33,34, Crowley CA35, Dashti HS3,36, Davies G37, Deary IJ37, Degenhardt F38,39, Derks EM29, Direk N40,41, Dolan CV11, Dunn EC42,43,44, Eley TC28, Eriksson N45, Escott-Price V46, Kiadeh FHF47, Finucane HK48,49, Forstner AJ38,39,50,51, Frank J52, Gaspar HA28, Gill M53, Giusti-Rodríguez P54, Goes FS55, Gordon SD56, Grove J6,7,8,57, Hall LS12,58, Hannon E59, Hansen CS8,19, Hansen TF60,61,62, Herms S38,39,51, Hickie IB63, Hoffmann P38,39,51, Homuth G64, Horn C65, Hottenga JJ11, Hougaard DM8,19, Hu M66, Hyde CL67, Ising M68, Jansen R20, Jin F69,70, Jorgenson E71, Knowles JA72, Kohane IS73,74,75, Kraft J5, Kretzschmar WW76, Krogh J77, Kutalik Z78,79, Lane JM3,36,80, Li Y76, Li Y35,54, Lind PA29, Liu X70, Lu L70, MacIntyre DJ81,82, MacKinnon DF55, Maier RM30, Maier W83, Marchini J84, Mbarek H11, McGrath P85, McGuffin P28, Medland SE29, Mehta D30,86, Middeldorp CM11,87,88, Mihailov E89, Milaneschi Y20, Milani L89, Mill J59, Mondimore FM55, Montgomery GW10, Mostafavi S90,91, Mullins N28, Nauck M92,93, Ng B91, Nivard MG11, Nyholt DR94, O'Reilly PF28, Oskarsson H95, Owen MJ96, Painter JN29, Pedersen CB8,13,14, Pedersen MG8,13,14, Peterson RE18,97, Pettersson E23, Peyrot WJ20, Pistis G27, Posthuma D98,99, Purcell SM100, Quiroz JA101, Qvist P6,7,8, Rice JP102, Riley BP18, Rivera M28,103, Saeed Mirza S41, Saxena R3,36,80, Schoevers R104, Schulte EC105,106, Shen L71, Shi J107, Shyn SI108, Sigurdsson E109, Sinnamon GBC110, Smit JH20, Smith DJ111, Stefansson H112, Steinberg S112, Stockmeier CA113, Streit F52, Strohmaier J52, Tansey KE114, Teismann H115, Teumer A116, Thompson W8,61,117,118, Thomson PA119, Thorgeirsson TE112, Tian C45, Traylor M120, Treutlein J52, Trubetskoy V5, Uitterlinden AG121, Umbricht D122, Van der Auwera S123, van Hemert AM124, Viktorin A23, Visscher PM10,30, Wang Y8,61,117, Webb BT125, Weinsheimer SM8,61, Wellmann J115, Willemsen G11, Witt SH52, Wu Y10, Xi HS126, Yang J10,30, Zhang F10; eQTLGen; 23andMe, Arolt V127, Baune BT15, Berger K115, Boomsma DI11, Cichon S38,51,128,129, Dannlowski U127, de Geus ECJ11,130, DePaulo JR55, Domenici E131, Domschke K132, Esko T3,89, Grabe HJ123, Hamilton SP133, Hayward C134, Heath AC102, Hinds DA45, Kendler KS18, Kloiber S68,135,136, Lewis G137, Li QS138, Lucae S68, Madden PFA102, Magnusson PK23, Martin NG56, McIntosh AM12,37, Metspalu A89,139, Mors O8,140, Mortensen PB7,8,13,14, Müller-Myhsok B16,17,141, Nordentoft M8,142, Nöthen MM38,39, O'Donovan MC96, Paciga SA143, Pedersen NL23, Penninx BWJH20, Perlis RH43,144, Porteous DJ119, Potash JB145, Preisig M27, Rietschel M52, Schaefer C71, Schulze TG52,55,106,146,147, Smoller JW42,43,44, Stefansson K112,148, Tiemeier H41,149,150, Uher R151, Völzke H116, Weissman MM85,152, Werge T8,61,153, Winslow AR154,155, Lewis CM28,156, Levinson DF157, Breen G28,158, Børglum AD6,7,8, Sullivan PF159,160,161; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.

Author information

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.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center