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

Tarjinder Singh*, James T.R. Walters, Mandy Johnstone, David Curtis, Jaana Suvisaari, Minna Torniainen, Elliott Rees, Conrad Iyegbe, Douglas Blackwood, Andrew M. McIntosh, Georg Kirov, Daniel Geschwind, Robin M. Murray, Marta Di Forti, Elvira Bramon, Michael Gandal, Christina M. Hultman, Pamela Sklar, Aarno Palotie, Patrick F. SullivanMichael C. O'Donovan, Michael J. Owen, Jeffrey C. Barrett

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

149 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1167-1173
Number of pages7
JournalNature Genetics
Issue number8
Early online date26 Jun 2017
Publication statusPublished - 1 Aug 2017


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