Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
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Abstract
Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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The record
- Venue
- Nature Genetics
- Topic
- Genetic Associations and Epidemiology
- Field
- Biochemistry, Genetics and Molecular Biology
- Canadian institutions
- Public Health OntarioMcGill UniversityDalhousie UniversityMontreal Neurological Institute and HospitalUniversity of TorontoCentre for Addiction and Mental HealthMcGill University Health Centre
- Funders
- National Institute of Mental HealthMedical Research CouncilInstitute of Psychiatry, Psychology and Neuroscience, King’s College LondonSchool of Medicine, Emory UniversityNational Institutes of HealthUniversité de ParisAssistance publique-Hôpitaux de ParisUniversity of Cape TownCentre d'Imagerie BioMédicaleUniversitat de BarcelonaHáskóli ÍslandsUniversitetet i OsloUmeå UniversitetUniversity of California, IrvineUniversidad Autónoma de MadridMcDonnell Center for Systems NeuroscienceUniversity of MelbourneUniversity of TorontoUniversity of GlasgowUniversity of New South WalesSouth African Medical Research CouncilUniversidad de GranadaKarolinska InstitutetSchool of Medicine, University of California, IrvineLundbeckfondenInstitut National de la Santé et de la Recherche MédicaleEmory UniversityWestfälische Wilhelms-Universität MünsterUniversity of OxfordNeuroscience Research AustraliaVanderbilt UniversityKing's College LondonDiakonhjemmetCentro de Biología Molecular Severo OchoaVanderbilt University Medical CenterPfizerNational Institute for Health and Care ResearchAgence Nationale de la RechercheUniversity of Southern CaliforniaWorld Health OrganizationU.S. Department of Health and Human Services
- Keywords
- BiologyGenome-wide association studyComputational biologyBipolar disorderGeneticsGenetic associationGenomeAssociation (psychology)Evolutionary biologySingle-nucleotide polymorphismGeneGenotypeNeuroscience
- Has abstract in OpenAlex
- yes