Mapping genomic loci implicates genes and synaptic biology in schizophrenia

• Verfasst von: Trubetskoy, Vassily [VerfasserIn]
• Verfasst von: Frank, Josef [VerfasserIn]
• Verfasst von: Streit, Fabian [VerfasserIn]
• Verfasst von: Witt, Stephanie [VerfasserIn]
• Verfasst von: Rietschel, Marcella [VerfasserIn]
• Verfasst von: Rujescu, Dan [VerfasserIn]
• Verfasst von: Bender, Stephan [VerfasserIn]
• Verfasst von: Weisbrod, Matthias [VerfasserIn]
• Titel: Mapping genomic loci implicates genes and synaptic biology in schizophrenia
• Mitwirkende: Dieterich, Daniela C. [MitwirkendeR]
• Mitwirkende: Pielot, Rainer [MitwirkendeR]
• Mitwirkende: Smalla, Karl-Heinz [MitwirkendeR]
• Verf.angabe: Vassily Trubetskoy, Josef Frank, Fabian Streit, Stephanie H. Witt, Marcella Rietschel, Dan Rujescu, Stephan Bender, Matthias Weisbrod [und viele weitere] & Schizophrenia Working Group of the Psychiatric Genomics Consortium ; Indonesia Schizophrenia Consortium, The SynGO Consortium [und einige weitere]
• E-Jahr: 2022
• Jahr: 8 April 2022
• Umfang: 24 S.
• Illustrationen: Diagramme
• Fussnoten: Psychosis Endophenotypes International Consortium: Maria J. Arranz, Stephan Bender, Dan Rujescu, Matthias Weisbrod [und 18 weitere] ; Schizophrenia Working Group of the Psychiatric Genomics Consortium: Vassily Trubetskoy [und viele weitere] ; Gesehen am 26.10.2022
• Titel Quelle: Enthalten in: Nature
• Ort Quelle: London [u.a.] : Nature Publ. Group, 1869
• Jahr Quelle: 2022
• Band/Heft Quelle: 604(2022), 7906 vom: Apr., Seite 502-508
• ISSN Quelle: 1476-4687
• DOI: doi:10.1038/s41586-022-04434-5
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Diseases of the nervous system
• Sach-SW: Genetics of the nervous system
• Sach-SW: Genome-wide association studies
• Sach-SW: Schizophrenia
• K10plus-PPN: 1820036685

Abstract

Schizophrenia has a heritability of 60-80%, 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.