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Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Citation

Trubetskoy, V and Pardinas, AF and Qi, T and Panagiotaropoulou, G and Neil, AL and Walters, JT and O'Donovan, MC, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Mapping genomic loci implicates genes and synaptic biology in schizophrenia, Nature, 604, (7906) pp. 502-508. ISSN 0028-0836 (2022) [Refereed Article]

Copyright Statement

The Author(s), under exclusive licence to Springer Nature Limited 2022.

DOI: doi:10.1038/s41586-022-04434-5

Abstract

Schizophrenia has a heritability of 6080%, 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.

Item Details

Item Type:Refereed Article
Keywords:Schizophrenia, GWAS, fine-mapping, functional genomic data, biological processes
Research Division:Biomedical and Clinical Sciences
Research Group:Clinical sciences
Research Field:Psychiatry (incl. psychotherapy)
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biomedical and clinical sciences
UTAS Author:Neil, AL (Associate Professor Amanda Neil)
ID Code:150535
Year Published:2022
Web of Science® Times Cited:57
Deposited By:Menzies Institute for Medical Research
Deposited On:2022-06-19
Last Modified:2022-07-29
Downloads:0

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