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The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability

Singh, Tarjinder, Walters, James T. R. ORCID:, Johnstone, Mandy, Curtis, David, Suvisaari, Jaana, Torniainen, Minna, Rees, Elliott ORCID:, Iyegbe, Conrad, Blackwood, Douglas, McIntosh, Andrew M., Kirov, George ORCID:, Geschwind, Daniel, Murray, Robin M, Di Forti, Marta, Bramon, Elvira, Gandal, Michael, Hultman, Christina M., Sklar, Pamela, Palotie, Aarno, Sullivan, Patrick F., O'Donovan, Michael C. ORCID:, Owen, Michael J. ORCID: and Barrett, Jeffrey C. 2017. The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Nature Genetics 49 , pp. 1167-1173. 10.1038/ng.3903

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By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In patients with schizophrenia who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known risk genes for neurodevelopmental disorders, a significant rare variant burden persists in other genes intolerant of loss-of-function variants; although this effect is notably stronger in patients with both schizophrenia and intellectual disability, it is also seen in patients with schizophrenia who do not have intellectual disability. Together, our results show that rare, damaging variants contribute to the risk of schizophrenia both with and without intellectual disability and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > R Medicine (General)
Additional Information: INTERVAL Study, UK10K Consortium
Publisher: Nature
ISSN: 1061-4036
Date of First Compliant Deposit: 7 June 2017
Date of Acceptance: 1 June 2017
Last Modified: 07 Nov 2023 21:06

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