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Hum Mol Genet. 2016 Aug 1;25(15):3383-3394. doi: 10.1093/hmg/ddw181. Epub 2016 Jun 21.

Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.

Hou L1, Bergen SE2,3, Akula N1, Song J2, Hultman CM2, Landén M4,2, Adli M5, Alda M6, Ardau R7, Arias B8, Aubry JM9, Backlund L10, Badner JA11, Barrett TB12, Bauer M13, Baune BT14, Bellivier F15, Benabarre A16, Bengesser S17, Berrettini WH18, Bhattacharjee AK19, Biernacka JM20,21, Birner A17, Bloss CS22, Brichant-Petitjean C15, Bui ET1, Byerley W23, Cervantes P24, Chillotti C7, Cichon S25,26,27,28, Colom F16, Coryell W29, Craig DW30, Cruceanu C31, Czerski PM32, Davis T14, Dayer A9, Degenhardt F25,26, Del Zompo M33, DePaulo JR34, Edenberg HJ35, Étain B36, Falkai P37, Foroud T38, Forstner AJ25,26, Frisén L39,40, Frye MA21, Fullerton JM41,42, Gard S43, Garnham JS6, Gershon ES11, Goes FS34, Greenwood TA19, Grigoroiu-Serbanescu M44, Hauser J32, Heilbronner U45,46, Heilmann-Heimbach S25,26, Herms S25,26,28, Hipolito M47, Hitturlingappa S14, Hoffmann P25,26,27,28, Hofmann A25,26, Jamain S36, Jiménez E16, Kahn JP48, Kassem L1, Kelsoe JR19, Kittel-Schneider S49, Kliwicki S50, Koller DL38, König B51, Lackner N17, Laje G1, Lang M52, Lavebratt C10, Lawson WB47, Leboyer M36, Leckband SG53, Liu C54, Maaser A25,26, Mahon PB34, Maier W55, Maj M56, Manchia M33,57, Martinsson L39, McCarthy MJ58, McElroy SL59, McInnis MG60, McKinney R19, Mitchell PB61, Mitjans M8, Mondimore FM34, Monteleone P56,62, Mühleisen TW25,26,27, Nievergelt CM19, Nöthen MM25,26, Novák T63, Nurnberger JI Jr64, Nwulia EA47, Ösby U65, Pfennig A13, Potash JB66, Propping P25, Reif A49, Reininghaus E17, Rice J67, Rietschel M52, Rouleau GA68, Rybakowski JK50, Schalling M10, Scheftner WA69, Schofield PR42,70, Schork NJ22, Schulze TG1,34,45,46,52, Schumacher J25,26, Schweizer BW34, Severino G33, Shekhtman T19, Shilling PD19, Simhandl C71, Slaney CM6, Smith EN22, Squassina A33, Stamm T5, Stopkova P63, Streit F52, Strohmaier J52, Szelinger S30, Tighe SK66, Tortorella A56, Turecki G31, Vieta E16, Volkert J49, Witt SH52, Wright A61, Zandi PP72, Zhang P60, Zollner S60, McMahon FJ73.

Author information

1
Intramural Research Program, National Institute of Mental Health, National Institutes of Health,U.S. Department of Health & Human Services, Bethesda, MD, USA.
2
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
3
Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4
Institute of Neuroscience and Physiology, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
5
Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
6
Department of Psychiatry, Dalhousie University, Halifax, Canada.
7
Unit of Clinical Pharmacology, Hospital University Agency of Cagliari, Cagliari, Italy.
8
Department of Biologia Animal, Unitat d'Antropologia (Dp. Biología Animal), Facultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, CIBERSAM, Barcelona, Spain.
9
Department of Mental Health and Psychiatry, Mood Disorders Unit, Geneva University Hospitals, Geneva, Switzerland.
10
Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
11
Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
12
Portland Veterans Affairs Medical Center, Portland, OR, USA.
13
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany.
14
Discipline of Psychiatry, University of Adelaide, Adelaide, Australia.
15
INSERM UMR-S 1144 - Université Paris Diderot. Pôle de Psychiatrie, AP-HP, Groupe Hospitalier Lariboisière-F. Widal, Paris, France.
16
Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
17
Special Outpatient Center for Bipolar Affective Disorder, Medical University of Graz, Graz, Austria.
18
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
19
Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
20
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
21
Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
22
Scripps Translational Science Institute, La Jolla, CA, USA.
23
Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA.
24
McGill University Health Centre, Mood Disorders Program, Montreal, QC, Canada.
25
Institute of Human Genetics, University of Bonn, Germany.
26
Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
27
Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Germany.
28
Division of Medical Genetics and Department of Biomedicine, University of Basel, Switzerland.
29
University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
30
The Translational Genomics Research Institute, Phoenix, AZ, USA.
31
Douglas Mental Health University Institute, McGill University, Montreal, Canada.
32
Psychiatric Genetic Unit, Poznan University of Medical Sciences, Poznan, Poland.
33
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
34
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
35
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
36
INSERM U955, Psychiatrie translationnelle, Université Paris Est Créteil, Pôle de Psychiatrie et d'Addictologie, Hôpitaux Universitaires Henri Mondor, Créteil, France.
37
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany.
38
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
39
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
40
Child and Adolescent Psychiatry Research Center, Stockholm, Sweden.
41
Psychiatric Genetics, Neuroscience Research Australia, Sydney, Australia.
42
School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
43
Service de Psychiatrie, Hôpital Charles Perrens, Bordeaux, France.
44
Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
45
Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.
46
Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.
47
Department of Psychiatry and Behavioral Sciences, Howard University Hospital, Washington, DC, USA.
48
Service de Psychiatrie et Psychologie Clinique, Centre Psychothérapique de Nancy - Université de Lorraine, Nancy, France.
49
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
50
Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
51
Department of Psychiatry and Psychotherapeuthic Medicine, Landesklinikum Neunkirchen, Neunkirchen, Austria.
52
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
53
Department of Pharmacy, VA San Diego Healthcare System, San Diego, CA, USA.
54
Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
55
Department of Psychiatry, University of Bonn, Germany.
56
Department of Psychiatry, University of Naples SUN, Naples, Italy.
57
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
58
Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.
59
Lindner Center of HOPE, University of Cincinnati College of Medicine, Mason, OH, USA.
60
Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
61
School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, Australia.
62
Neurosciences Section, Department of Medicine and Surgery, University of Salerno, Salerno, Italy.
63
National Institute of Mental Health, Klecany, Czech Republic.
64
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
65
Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
66
Department of Psychiatry, Carver College of Medicine, University of Iowa School of Medicine, Iowa City, IA, USA.
67
Department of Psychiatry, Washington University School of Medicine in St. Louis.
68
Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.
69
Rush University Medical Center, Chicago, IL, USA.
70
Mental Illness, Neuroscience Research Australia, Sydney, Australia.
71
Bipolar Center Wiener Neustadt, Wiener Neustadt, Austria and.
72
Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
73
Intramural Research Program, National Institute of Mental Health, National Institutes of Health,U.S. Department of Health & Human Services, Bethesda, MD, USA, mcmahonf@mail.nih.gov.

Abstract

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P =  5.87 × 10 -9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P =  4.53 × 10 -9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

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