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Rare coding variants in ten genes confer substantial risk for schizophrenia

Singh, Tarjinder, Schizophrenia Exome Meta-Analysis (SCHEMA) Consortium, Kirov, George ORCID:, Rees, Elliott ORCID:, Walters, James ORCID:, Owen, Michael ORCID: and O'Donovan, Michael ORCID: 2022. Rare coding variants in ten genes confer substantial risk for schizophrenia. Nature 604 , pp. 509-516. 10.1038/s41586-022-04556-w

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Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-d-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Nature Research
ISSN: 0028-0836
Date of First Compliant Deposit: 8 April 2022
Date of Acceptance: 16 February 2022
Last Modified: 01 Jun 2023 22:18

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