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Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Stahl EA1,2,3, Breen G4,5, Forstner AJ6,7,8,9,10, McQuillin A11, Ripke S12,13,14, Trubetskoy V13, Mattheisen M15,16,17,18,19, Wang Y20,21, Coleman JRI4,5, Gaspar HA4,5, de Leeuw CA22, Steinberg S23, Pavlides JMW24, Trzaskowski M25, Byrne EM25, Pers TH26,27, Holmans PA28, Richards AL28, Abbott L12, Agerbo E19,29, Akil H30, Albani D31, Alliey-Rodriguez N32, Als TD15,16,19, Anjorin A33, Antilla V14, Awasthi S13, Badner JA34, Bækvad-Hansen M19,35, Barchas JD36, Bass N11, Bauer M37, Belliveau R12, Bergen SE38, Pedersen CB19,29, Bøen E39, Boks MP40, Boocock J41, Budde M42, Bunney W43, Burmeister M44, Bybjerg-Grauholm J19,35, Byerley W45, Casas M46,47,48,49, Cerrato F12, Cervantes P50, Chambert K12, Charney AW51, Chen D12, Churchhouse C12,14, Clarke TK52, Coryell W53, Craig DW54, Cruceanu C50,55, Curtis D56,57, Czerski PM58, Dale AM59,60,61,62, de Jong S4,5, Degenhardt F8, Del-Favero J63, DePaulo JR64, Djurovic S65,66, Dobbyn AL67,51, Dumont A12, Elvsåshagen T68,69, Escott-Price V28, Fan CC62, Fischer SB6,10, Flickinger M70, Foroud TM71, Forty L28, Frank J72, Fraser C28, Freimer NB73, Frisén L74,75,76, Gade K42,77, Gage D12, Garnham J78, Giambartolomei C79, Pedersen MG19,29, Goldstein J12, Gordon SD80, Gordon-Smith K81, Green EK82, Green MJ83,84, Greenwood TA61, Grove J15,16,19,85, Guan W86, Guzman-Parra J87, Hamshere ML28, Hautzinger M88, Heilbronner U42, Herms S6,8,10, Hipolito M89, Hoffmann P6,8,10, Holland D59,90, Huckins L67,51, Jamain S91,92, Johnson JS67,51, Juréus A38, Kandaswamy R4, Karlsson R38, Kennedy JL93,94,95,96, Kittel-Schneider S97, Knowles JA98,99, Kogevinas M100, Koller AC8, Kupka R101,102,103, Lavebratt C74, Lawrence J104, Lawson WB89, Leber M105, Lee PH12,14,106, Levy SE107, Li JZ108, Liu C109, Lucae S110, Maaser A8, MacIntyre DJ111,112, Mahon PB64,113, Maier W114, Martinsson L75, McCarroll S12,115, McGuffin P4, McInnis MG116, McKay JD117, Medeiros H99, Medland SE80, Meng F30,116, Milani L118, Montgomery GW25, Morris DW119,120, Mühleisen TW6,121, Mullins N4, Nguyen H67,51, Nievergelt CM61,122, Adolfsson AN123, Nwulia EA89, O'Donovan C78, Loohuis LMO73, Ori APS73, Oruc L124, Ösby U125, Perlis RH126,127, Perry A81, Pfennig A37, Potash JB64, Purcell SM51,113, Regeer EJ128, Reif A97, Reinbold CS6,10, Rice JP129, Rivas F87, Rivera M4,130, Roussos P67,51,131, Ruderfer DM132, Ryu E133, Sánchez-Mora C46,47,49, Schatzberg AF134, Scheftner WA135, Schork NJ136, Shannon Weickert C83,84, Shehktman T61, Shilling PD61, Sigurdsson E137, Slaney C78, Smeland OB138,139, Sobell JL140, Søholm Hansen C19,35, Spijker AT141, St Clair D142, Steffens M143, Strauss JS95,144, Streit F72, Strohmaier J72, Szelinger S145, Thompson RC116, Thorgeirsson TE23, Treutlein J72, Vedder H146, Wang W67,51, Watson SJ116, Weickert TW83,84, Witt SH72, Xi S147, Xu W148,149, Young AH150, Zandi P151, Zhang P152, Zöllner S116; eQTLGen Consortium; BIOS Consortium, Adolfsson R123, Agartz I17,39,153, Alda M78,154, Backlund L75, Baune BT155,156, Bellivier F157,158,159,160, Berrettini WH161, Biernacka JM133, Blackwood DHR52, Boehnke M70, Børglum AD15,16,19, Corvin A120, Craddock N28, Daly MJ12,14, Dannlowski U156, Esko T26,115,118,162, Etain B157,159,160,163, Frye M164, Fullerton JM84,165, Gershon ES32,166, Gill M120, Goes F64, Grigoroiu-Serbanescu M167, Hauser J58, Hougaard DM19,35, Hultman CM38, Jones I28, Jones LA81, Kahn RS51,40, Kirov G28, Landén M38,168, Leboyer M92,157,169, Lewis CM4,5,170, Li QS171, Lissowska J172, Martin NG80,173, Mayoral F87, McElroy SL174, McIntosh AM52,175, McMahon FJ176, Melle I177, Metspalu A118,178, Mitchell PB83, Morken G179,180, Mors O19,181, Mortensen PB15,19,29, Müller-Myhsok B55,182,183, Myers RM107, Neale BM26,12,14, Nimgaonkar V184, Nordentoft M19,185, Nöthen MM8, O'Donovan MC28, Oedegaard KJ186,187, Owen MJ28, Paciga SA188, Pato C99,189, Pato MT99, Posthuma D22,190, Ramos-Quiroga JA46,47,48,49, Ribasés M46,47,49, Rietschel M72, Rouleau GA191,192, Schalling M74, Schofield PR84,165, Schulze TG42,64,72,77,176, Serretti A193, Smoller JW12,194,106, Stefansson H23, Stefansson K23,137, Stordal E195,196, Sullivan PF38,197,198, Turecki G199, Vaaler AE200, Vieta E201, Vincent JB144, Werge T19,202,203, Nurnberger JI204, Wray NR24,25, Di Florio A28,198, Edenberg HJ205, Cichon S6,8,10,121, Ophoff RA40,41,73, Scott LJ70, Andreassen OA138,139, Kelsoe J206, Sklar P67,51,152; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium.

Author information

1
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. eli.stahl@mssm.edu.
2
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. eli.stahl@mssm.edu.
3
Medical and Population Genetics, Broad Institute, Cambridge, MA, USA. eli.stahl@mssm.edu.
4
MRC Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
5
NIHR BRC for Mental Health, King's College London, London, UK.
6
Department of Biomedicine, University of Basel, Basel, Switzerland.
7
Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
8
Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany.
9
Centre for Human Genetics, University of Marburg, Marburg, Germany.
10
Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
11
Division of Psychiatry, University College London, London, UK.
12
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
13
Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany.
14
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
15
iSEQ, Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
16
Department of Biomedicine-Human Genetics, Aarhus University, Aarhus, Denmark.
17
Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
18
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Würzburg, Germany.
19
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
20
Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen, Denmark.
21
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
22
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
23
deCODE Genetics/Amgen, Reykjavik, Iceland.
24
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
25
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
26
Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
27
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA.
28
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, England.
29
National Centre for Register-based Research and Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark.
30
Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
31
Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
32
Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
33
Department of Psychiatry, Berkshire Healthcare NHS Foundation Trust, Bracknell, UK.
34
Department of Psychiatry, Rush University Medical Center, Chicago, IL, USA.
35
Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
36
Department of Psychiatry, Weill Cornell Medical College, New York, NY, USA.
37
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
38
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
39
Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
40
Psychiatry, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, the Netherlands.
41
Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
42
Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Munich, Germany.
43
Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA, USA.
44
Molecular & Behavioral Neuroscience Institute and Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
45
Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
46
Instituto de Salud Carlos III, Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain.
47
Department of Psychiatry, Hospital Universitari Vall d´Hebron, Barcelona, Spain.
48
Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
49
Psychiatric Genetics Unit, Group of Psychiatry Mental Health and Addictions, Vall d´Hebron Research Institut, Universitat Autònoma de Barcelona, Barcelona, Spain.
50
Department of Psychiatry, Mood Disorders Program, McGill University Health Center, Montreal, Quebec, Canada.
51
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
52
Division of Psychiatry, University of Edinburgh, Edinburgh, Scotland.
53
University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
54
Translational Genomics, USC, Phoenix, AZ, USA.
55
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
56
Centre for Psychiatry, Queen Mary University of London, London, UK.
57
UCL Genetics Institute, University College London, London, UK.
58
Department of Psychiatry, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, Poland.
59
Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
60
Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
61
Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
62
Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA.
63
Applied Molecular Genomics Unit, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
64
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
65
Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo, Norway.
66
NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
67
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
68
Department of Neurology, Oslo University Hospital, Oslo, Norway.
69
NORMENT, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.
70
Center for Statistical Genetics and Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
71
Department of Medical & Molecular Genetics, Indiana University, Indianapolis, IN, USA.
72
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
73
Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
74
Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
75
Department of Clinical Neuroscience, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
76
Child and Adolescent Psychiatry Research Center, Stockholm, Sweden.
77
Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
78
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
79
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
80
Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
81
Department of Psychological Medicine, University of Worcester, Worcester, UK.
82
School of Biomedical Sciences, Plymouth University Peninsula Schools of Medicine and Dentistry, University of Plymouth, Plymouth, UK.
83
School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
84
Neuroscience Research Australia, Sydney, New South Wales, Australia.
85
Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
86
Biostatistics, University of Minnesota System, Minneapolis, MN, USA.
87
Mental Health Department, University Regional Hospital, Biomedicine Institute (IBIMA), Málaga, Spain.
88
Department of Psychology, Eberhard Karls Universität Tübingen, Tubingen, Germany.
89
Department of Psychiatry and Behavioral Sciences, Howard University Hospital, Washington, DC, USA.
90
Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, USA.
91
Psychiatrie Translationnelle, Inserm U955, Créteil, France.
92
Faculté de Médecine, Université Paris Est, Créteil, France.
93
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Onatario, Canada.
94
Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
95
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
96
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
97
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
98
Cell Biology, SUNY Downstate Medical Center College of Medicine, Brooklyn, NY, USA.
99
Institute for Genomic Health, SUNY Downstate Medical Center College of Medicine, Brooklyn, NY, USA.
100
ISGlobal, Barcelona, Spain.
101
Psychiatry, Altrecht, Utrecht, the Netherlands.
102
Psychiatry, GGZ inGeest, Amsterdam, the Netherlands.
103
Psychiatry, VU Medisch Centrum, Amsterdam, the Netherlands.
104
Department of, rth East London NHS Foundation Trust, Ilford, UK.
105
Department of Neurodegenerative Diseases and Geropsychiatry, University Hospital Bonn, Bonn, Germany.
106
Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
107
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
108
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
109
Department of Psychiatry, University of Illinois at Chicago College of Medicine, Chicago, IL, USA.
110
Max Planck Institute of Psychiatry, Munich, Germany.
111
Mental Health, NHS 24, Glasgow, UK.
112
Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
113
Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA.
114
Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
115
Department of Genetics, Harvard Medical School, Boston, MA, USA.
116
Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
117
Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France.
118
Estonian Genome Center, University of Tartu, Tartu, Estonia.
119
Discipline of Biochemistry, Neuroimaging and Cognitive Genomics (NICOG) Centre, National University of Ireland, Galway, Galway, Ireland.
120
Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
121
Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany.
122
Research/Psychiatry, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
123
Department of Clinical Sciences, Psychiatry, Umeå University Medical Faculty, Umeå, Sweden.
124
Department of Clinical Psychiatry, Psychiatry Clinic, Clinical Center University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
125
Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
126
Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
127
Division of Clinical Research, Massachusetts General Hospital, Boston, MA, USA.
128
Outpatient Clinic for Bipolar Disorder, Altrecht, Utrecht, the Netherlands.
129
Department of Psychiatry, Washington University in Saint Louis, Saint Louis, MO, USA.
130
Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain.
131
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
132
Medicine, Psychiatry, Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
133
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
134
Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.
135
Rush University Medical Center, Chicago, IL, USA.
136
Scripps Translational Science Institute, La Jolla, CA, USA.
137
Faculty of Medicine, Department of Psychiatry, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
138
Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
139
NORMENT, University of Oslo, Oslo, Norway.
140
Psychiatry and the Behavioral Sciences, University of Southern California, Los Angeles, CA, USA.
141
Mood Disorders, PsyQ, Rotterdam, the Netherlands.
142
Institute for Medical Sciences, University of Aberdeen, Aberdeen, UK.
143
Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.
144
Centre for Addiction and Mental Health, Toronto, Onatario, Canada.
145
Neurogenomics, TGen, Phoenix, AZ, USA.
146
Department of Psychiatry, Psychiatrisches Zentrum Nordbaden, Wiesloch, Germany.
147
Computational Sciences Center of Emphasis, Pfizer Global Research and Development, Cambridge, MA, USA.
148
Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Onatario, Canada.
149
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
150
Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
151
Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
152
Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
153
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Institute of Clinical Medicine and Diakonhjemmet Hospital, University of Oslo, Oslo, Norway.
154
National Institute of Mental Health, Klecany, Czech Republic.
155
Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia.
156
Department of Psychiatry, University of Munster, Munster, Germany.
157
Department of Psychiatry and Addiction Medicine, Assistance Publique-Hopitaux de Paris, Paris, France.
158
Paris Bipolar and TRD Expert Centres, FondaMental Foundation, Paris, France.
159
UMR-S1144 Team 1: Biomarkers of relapse and therapeutic response in addiction and mood disorders, INSERM, Paris, France.
160
Department of Psychiatry, Université Paris Diderot, Paris, France.
161
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
162
Division of Endocrinology, Children's Hospital Boston, Boston, MA, USA.
163
Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
164
Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA.
165
School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
166
Department of Human Genetics, University of Chicago, Chicago, IL, USA.
167
Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
168
Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
169
INSERM, Paris, France.
170
Department of Medical & Molecular Genetics, King's College London, London, UK.
171
Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, USA.
172
Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland.
173
School of Psychology, The University of Queensland, Brisbane, Queensland, Australia.
174
Research Institute, Lindner Center of HOPE, Mason, OH, USA.
175
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
176
Human Genetics Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA.
177
Division of Mental Health and Addiction and Institute of Clinical Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway.
178
Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
179
Mental Health, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology-NTNU, Trondheim, Norway.
180
Department of Psychiatry, St Olavs University Hospital, Trondheim, Norway.
181
Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark.
182
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
183
University of Liverpool, Liverpool, UK.
184
Psychiatry and Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
185
Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.
186
Division of Psychiatry, Haukeland Universitetssjukehus, Bergen, Norway.
187
Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
188
Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Groton, CT, USA.
189
College of Medicine Institute for Genomic Health, SUNY Downstate Medical Center College of Medicine, Brooklyn, NY, USA.
190
Department of Clinical Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.
191
Department of Neurology and Neurosurgery, McGill University, Faculty of Medicine, Montreal, Quebec, Canada.
192
Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada.
193
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
194
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
195
Department of Psychiatry, Hospital Namsos, Namsos, Norway.
196
Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway.
197
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
198
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
199
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
200
Department of Psychiatry, Sankt Olavs Hospital Universitetssykehuset i Trondheim, Trondheim, Norway.
201
Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
202
Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.
203
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
204
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
205
Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
206
Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA. jkelsoe@ucsd.edu.

Abstract

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

PMID:
31043756
DOI:
10.1038/s41588-019-0397-8

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