Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.

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

Black Dog Institute Prince of Wales Hospital Randwick Australia

Center for Research in Environmental Epidemiology Barcelona Spain

Center of Psychiatry Weinsberg Weinsberg Germany

Département des sciences fondamentales Université du Québec à Chicoutimi Saguenay Canada

Department of Biology Medical Genetics and Ecology Kursk State Medical University Kursk Russian Federation

Department of Biomedicine and Centre for integrative Sequencing iSEQ Aarhus University Aarhus Denmark

Department of Cancer Epidemiology and Prevention Maria Sklodowska Curie Memorial Cancer Centre and Institute of Oncology Warsaw Warsaw Poland

Department of Epidemiology Nofer Institute of Occupational Medicine Lodz Poland

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

Department of Genetics and Fundamental Medicine of Bashkir State University Ufa Russian Federation

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

Department of Human Genetics McGill University Montreal Canada

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

Department of Psychiatry and Psychotherapy University of Cologne Cologne Germany

Department of Psychiatry Dalhousie University Halifax Canada

Department of Psychiatry Hospital Regional Universitario Biomedical Institute of Malaga Malaga Spain

Department of Psychiatry McGill University Montreal Canada

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

Department of Psychiatry University of Basel Basel Switzerland

Department of Psychiatry University of Bonn Bonn Germany

Department of Psychology Clinical Psychology and Psychotherapy Eberhard Karls University Tübingen Tübingen Germany

Genetic Cancer Susceptibility Group International Agency for Research on Cancer Lyon France

Genetic Epidemiology Group International Agency for Research on Cancer Lyon France

German Center for Neurodegenerative Diseases Bonn Germany

Human Genomics Research Group Department of Biomedicine University of Basel Basel Switzerland

Institute for Genomics Mathematics University of Bonn Bonn Germany

Institute for Medical Biometry Informatics and Epidemiology University of Bonn Bonn Germany

Institute of Biochemistry and Genetics Ufa Scientific Center of Russian Academy of Sciences Ufa Russian Federation

Institute of Human Genetics University of Bonn Bonn Germany

Institute of Medical Genetics and Pathology University Hospital Basel Basel Switzerland

Institute of Medical Informatics Biometry and Epidemiology University Duisburg Essen Essen Germany

Institute of Medical Microbiology Immunology and Parasitology University of Bonn Bonn Germany

Institute of Neuroscience and Medicine Research Center Juelich Juelich Germany

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

Institute of Pulmonology Russian State Medical University Moscow Russian Federation

Laboratory of Psychiatric Genetics Department of Psychiatry Poznan University of Medical Sciences Poznan Poland

Max Planck Institute of Psychiatry Munich Germany

McGill Group for Suicide Studies and Douglas Research Institute Montreal Canada

Montreal Neurological Institute McGill University Montreal Canada

Moscow Research Institute of Psychiatry Moscow Russian Federation

Munich Cluster for Systems Neurology Munich Germany

National Centre Register Based Research Aarhus University Aarhus Denmark

National Institute of Mental Health Klecany Czech Republic

Neuroscience Research Australia Sydney Australia

Psychiatric Center Nordbaden Wiesloch Germany

Queensland Institute of Medical Research Brisbane Australia

Research Institute for Genetic and Molecular Epidemiology Kursk State Medical University Kursk Russian Federation

Russian Academy of Medical Sciences Mental Health Research Center Moscow Russian Federation

School of Medical Sciences Faculty of Medicine University of New South Wales Sydney Australia

School of Psychiatry University of New South Wales Randwick Australia

The Lundbeck Foundation Initiative for integrative Psychiatric Research iPSYCH Aarhus and Copenhagen Denmark

University of Liverpool Institute of Translational Medicine Liverpool United Kingdom

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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study