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Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Journal Article


Abstract


  • 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.

Publication Date


  • 2022

Published In


Citation


  • Trubetskoy, V., Pardi��as, A. F., Qi, T., Panagiotaropoulou, G., Awasthi, S., Bigdeli, T. B., . . . Gershon, E. S. (2022). Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature, 604(7906), 502-508. doi:10.1038/s41586-022-04434-5

Scopus Eid


  • 2-s2.0-85127650703

Web Of Science Accession Number


Start Page


  • 502

End Page


  • 508

Volume


  • 604

Issue


  • 7906

Place Of Publication


Abstract


  • 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.

Publication Date


  • 2022

Published In


Citation


  • Trubetskoy, V., Pardi��as, A. F., Qi, T., Panagiotaropoulou, G., Awasthi, S., Bigdeli, T. B., . . . Gershon, E. S. (2022). Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature, 604(7906), 502-508. doi:10.1038/s41586-022-04434-5

Scopus Eid


  • 2-s2.0-85127650703

Web Of Science Accession Number


Start Page


  • 502

End Page


  • 508

Volume


  • 604

Issue


  • 7906

Place Of Publication