The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Singh, T., Walters, J. T. R., Johnstone, M., Curtis, D., Suvisaari, J., Torniainen, M., Rees, E., Iyegbe, C., Blackwood, D., McIntosh, A. M., Kirov, G., Geschwind, D., Murray, R. M., Di Forti, M., Bramon, E., Gandal, M., Hultman, C. M., Sklar, P., INTERVAL Study, UK10K Consortium, Palotie, A., Sullivan, P. F., O'Donovan, M. C., Owen, M. J., & Barrett, J. C. Nature Genetics, 49(8):1167–1173, August, 2017. 00000
doi  abstract   bibtex   
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.
@article{singh_contribution_2017,
	title = {The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability},
	volume = {49},
	issn = {1546-1718},
	doi = {10.1038/ng.3903},
	abstract = {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.},
	language = {eng},
	number = {8},
	journal = {Nature Genetics},
	author = {Singh, Tarjinder and Walters, James T. R. and Johnstone, Mandy and Curtis, David and Suvisaari, Jaana and Torniainen, Minna and Rees, Elliott and Iyegbe, Conrad and Blackwood, Douglas and McIntosh, Andrew M. and Kirov, Georg and Geschwind, Daniel and Murray, Robin M. and Di Forti, Marta and Bramon, Elvira and Gandal, Michael and Hultman, Christina M. and Sklar, Pamela and {INTERVAL Study} and {UK10K Consortium} and Palotie, Aarno and Sullivan, Patrick F. and O'Donovan, Michael C. and Owen, Michael J. and Barrett, Jeffrey C.},
	month = aug,
	year = {2017},
	pmid = {28650482},
	pmcid = {PMC5533219},
	note = {00000 },
	keywords = {Case-Control Studies, Exome, Genetic Predisposition to Disease, Genetic Variation, Genotyping Techniques, Humans, Intellectual Disability, Mutation, Neurodevelopmental Disorders, Polymorphism, Single Nucleotide, Schizophrenia, Sequence Analysis, DNA},
	pages = {1167--1173}
}
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