title: Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.
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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authors.affiliation: Institute of Human Genetics, University of Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.|Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Germany.
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authors.affiliation: Intramural Research Program, National Institute of Mental Health, National Institutes of Health,U.S. Department of Health & Human Services, Bethesda, MD, USA.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.|Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.|Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August University Göttingen, Göttingen, Germany.|Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
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authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
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authors.initials: G
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authors.affiliation: Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
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authors.initials: PD
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authors.initials: C
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authors.affiliation: Department of Psychiatry, Dalhousie University, Halifax, Canada.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Slaney
authors.affiliation: Scripps Translational Science Institute, La Jolla, CA, USA.
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authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
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authors.affiliation: Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
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authors.lastname: Stamm
authors.affiliation: National Institute of Mental Health, Klecany, Czech Republic.
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authors.initials: P
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authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Fabian
authors.initials: F
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authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
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authors.affiliation: The Translational Genomics Research Institute, Phoenix, AZ, USA.
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authors.lastname: Szelinger
authors.affiliation: Department of Psychiatry, Carver College of Medicine, University of Iowa School of Medicine, Iowa City, IA, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Tighe
authors.affiliation: Department of Psychiatry, University of Naples SUN, Naples, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Tortorella
authors.affiliation: Douglas Mental Health University Institute, McGill University, Montreal, Canada.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
authors.affiliation: Bipolar Disorder Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Vieta
authors.affiliation: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Volkert
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: School of Psychiatry, University of New South Wales, and Black Dog Institute, Sydney, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Wright
authors.affiliation: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Zandi
authors.affiliation: Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zollner
authors.affiliation: 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.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: McMahon
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human