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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 -4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P -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.

Original publication

DOI

10.1038/s41588-019-0397-8

Type

Journal article

Journal

Nature genetics

Publication Date

05/2019

Volume

51

Pages

793 - 803

Addresses

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. eli.stahl@mssm.edu.

Keywords

eQTLGen Consortium, BIOS Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Humans, Genetic Predisposition to Disease, Case-Control Studies, Bipolar Disorder, Depressive Disorder, Major, Psychotic Disorders, Schizophrenia, Systems Biology, Polymorphism, Single Nucleotide, Female, Male, Genome-Wide Association Study, Genetic Loci