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.

Analytic and Translational Genetics Unit Massachusetts General Hospital Boston MA USA

Applied Molecular Genomics Unit VIB Department of Molecular Genetics University of Antwerp Antwerp Belgium

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

Bioinformatics Research Centre Aarhus University Aarhus Denmark

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

Biostatistics University of Minnesota System Minneapolis MN USA

Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health Toronto Onatario Canada

Cancer Epidemiology and Prevention M Sklodowska Curie Cancer Center and Institute of Oncology Warsaw Poland

Cell Biology SUNY Downstate Medical Center College of Medicine Brooklyn NY USA

Center for Multimodal Imaging and Genetics University of California San Diego La Jolla CA USA

Center for Neonatal Screening Department for Congenital Disorders Statens Serum Institut Copenhagen Denmark

Center for Neurobehavioral Genetics University of California Los Angeles Los Angeles CA USA

Center for Statistical Genetics and Department of Biostatistics University of Michigan Ann Arbor MI USA

Centre for Addiction and Mental Health Toronto Onatario Canada

Centre for Affective Disorders Institute of Psychiatry Psychology and Neuroscience London UK

Centre for Cognitive Ageing and Cognitive Epidemiology University of Edinburgh Edinburgh UK

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