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.

Biometric Psychiatric Genetics Research Unit Alexandru Obregia Clinical Psychiatric Hospital Bucharest Romania

Bipolar Center Wiener Neustadt Wiener Neustadt Austria and

Bipolar Disorder Program Institute of Neuroscience Hospital Clinic University of Barcelona IDIBAPS CIBERSAM Barcelona Catalonia Spain

Child and Adolescent Psychiatry Research Center Stockholm Sweden

Department of Adult Psychiatry Poznan University of Medical Sciences Poznan Poland

Department of Biochemistry and Molecular Biology Indiana University School of Medicine Indianapolis IN USA

Department of Biologia Animal Unitat d'Antropologia Universitat de Barcelona CIBERSAM Barcelona Spain

Department of Biomedical Sciences University of Cagliari Cagliari Italy

Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Department of Genetic Epidemiology in Psychiatry Central Institute of Mental Health Medical Faculty Mannheim University of Heidelberg Mannheim Germany

Department of Genomics Life and Brain Center University of Bonn Bonn Germany

Department of Health Sciences Research Mayo Clinic Rochester MN USA

Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN USA

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Mental Health and Psychiatry Mood Disorders Unit Geneva University Hospitals Geneva Switzerland

Department of Mental Health Johns Hopkins Bloomberg School of Public Health Baltimore MD USA

Department of Molecular Medicine and Surgery Karolinska Institutet and Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden

Department of Neurobiology Care Sciences and Society Karolinska Institutet and Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden

Department of Pharmacology Dalhousie University Halifax NS Canada

Department of Pharmacy VA San Diego Healthcare System San Diego CA USA

Department of Psychiatry and Behavioral Neuroscience University of Chicago Chicago IL USA

Department of Psychiatry and Behavioral Sciences Howard University Hospital Washington DC USA

Department of Psychiatry and Behavioral Sciences Johns Hopkins School of Medicine Baltimore MD USA

Department of Psychiatry and Psychology Mayo Clinic Rochester MN USA

Department of Psychiatry and Psychotherapeuthic Medicine Landesklinikum Neunkirchen Neunkirchen Austria

Department of Psychiatry and Psychotherapy Charité Universitätsmedizin Berlin Campus Charité Mitte Berlin Germany

Department of Psychiatry and Psychotherapy Ludwig Maximilians University Munich Munich Germany

Department of Psychiatry and Psychotherapy University Hospital Carl Gustav Carus Technische Universität Dresden Germany

Department of Psychiatry and Psychotherapy University Medical Center Georg August University Göttingen Göttingen Germany

Department of Psychiatry Carver College of Medicine University of Iowa School of Medicine Iowa City IA USA

Department of Psychiatry Dalhousie University Halifax Canada

Department of Psychiatry Indiana University School of Medicine Indianapolis IN USA

Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt Frankfurt Germany

Department of Psychiatry University of Bonn Germany

Department of Psychiatry University of California at San Francisco San Francisco CA USA

Department of Psychiatry University of California San Diego San Diego CA USA

Department of Psychiatry University of Illinois at Chicago Chicago IL USA

Department of Psychiatry University of Michigan Ann Arbor MI USA

Department of Psychiatry University of Naples SUN Naples Italy

Department of Psychiatry University of Pennsylvania Philadelphia PA USA

Department of Psychiatry VA San Diego Healthcare System San Diego CA USA

Department of Psychiatry Washington University School of Medicine in St Louis

Discipline of Psychiatry University of Adelaide Adelaide Australia

Division of Medical Genetics and Department of Biomedicine University of Basel Switzerland

Douglas Mental Health University Institute McGill University Montreal Canada

INSERM U955 Psychiatrie translationnelle Université Paris Est Créteil Pôle de Psychiatrie et d'Addictologie Hôpitaux Universitaires Henri Mondor Créteil France

INSERM UMR S 1144 Université Paris Diderot Pôle de Psychiatrie AP HP Groupe Hospitalier Lariboisière F Widal Paris France

Institute of Human Genetics University of Bonn Germany

Institute of Neuroscience and Medicine Research Centre Jülich Germany

Institute of Neuroscience and Physiology The Sahlgrenska Academy at Gothenburg University Gothenburg Sweden

Institute of Psychiatric Phenomics and Genomics Ludwig Maximilians University Munich Munich Germany

Intramural Research Program National Institute of Mental Health National Institutes of Health U S Department of Health and Human Services Bethesda MD USA

Lindner Center of HOPE University of Cincinnati College of Medicine Mason OH USA

McGill University Health Centre Mood Disorders Program Montreal QC Canada

Mental Illness Neuroscience Research Australia Sydney Australia

Montreal Neurological Institute and Hospital McGill University Montreal Canada

National Institute of Mental Health Klecany Czech Republic

Neurosciences Section Department of Medicine and Surgery University of Salerno Salerno Italy

Portland Veterans Affairs Medical Center Portland OR USA

Psychiatric Genetic Unit Poznan University of Medical Sciences Poznan Poland

Psychiatric Genetics Neuroscience Research Australia Sydney Australia

Rush University Medical Center Chicago IL USA

School of Medical Sciences University of New South Wales Sydney NSW 2052 Australia

School of Psychiatry University of New South Wales and Black Dog Institute Sydney Australia

Scripps Translational Science Institute La Jolla CA USA

Service de Psychiatrie et Psychologie Clinique Centre Psychothérapique de Nancy Université de Lorraine Nancy France

Service de Psychiatrie Hôpital Charles Perrens Bordeaux France

Special Outpatient Center for Bipolar Affective Disorder Medical University of Graz Graz Austria

Stanley Center for Psychiatric Research The Broad Institute of MIT and Harvard Cambridge MA USA

The Translational Genomics Research Institute Phoenix AZ USA

Unit of Clinical Pharmacology Hospital University Agency of Cagliari Cagliari Italy

University of Iowa Hospitals and Clinics Iowa City IA USA

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