Mapping genomic loci implicates genes and synaptic biology in schizophrenia
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Résumé
Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies. A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.
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La notice
- Revue
- Nature
- Thématique
- Genetic Associations and Epidemiology
- Domaine
- Biochemistry, Genetics and Molecular Biology
- Établissements canadiens
- Montreal Neurological Institute and HospitalDalhousie UniversityUniversity of TorontoCentre for Addiction and Mental HealthQueen's UniversityMcGill University
- Organismes subventionnaires
- National Institute of Neurological Disorders and StrokeEuropean Regional Development FundInstituto de Salud Carlos IIIEconomic and Social Research CouncilMedical Research CouncilStanley Center for Psychiatric Research, Broad InstituteNational Institute of Mental HealthHorizon 2020 Framework ProgrammeNational Institutes of HealthQingdao UniversityInnovative Medicines InitiativeChinese Academy of SciencesNational Alliance for Research on Schizophrenia and DepressionCentro de Investigación Biomédica en Red de Salud MentalShanghai Jiao Tong UniversityCardiff UniversityLundbeckfondenFundação de Amparo à Pesquisa do Estado de São PauloCoordenação de Aperfeiçoamento de Pessoal de Nível SuperiorNational Natural Science Foundation of ChinaWellcome TrustUniversity College LondonNational Medical Research CouncilKing's College LondonEuropean CommissionMinisterio de Ciencia e InnovaciónNational Institute for Health and Care ResearchNemzeti Kutatási Fejlesztési és Innovációs HivatalSouth London and Maudsley NHS Foundation TrustJohns Hopkins UniversityUniversity College London Hospitals NHS Foundation TrustBroad InstituteMental Health Research UKFundación Alicia KoplowitzNorges ForskningsrådAcademy of Medical Sciences
- Mots-clés
- BiologySchizophrenia (object-oriented programming)GeneComputational biologyGeneticsGenomicsEvolutionary biologyNeuroscienceGenomeComputer science
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