Journal
NATURE GENETICS
Volume 49, Issue 8, Pages 1167-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/ng.3903
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Categories
Funding
- Wellcome Trust [WT091310, WT098051, 072894/Z/03/Z, 090532/Z/09/Z, 075491/Z/04/B]
- Williams College Dr. Herchel Smith Fellowship
- Academy of Finland [251704, 286500]
- NIMH [U01MH105666, R01 MH077139, MH 41953, MH083094]
- Sigrid Juselius Foundation
- Medical Research Council (MRC) [G0801418, G0800509]
- Swedish Research Council [D0886501]
- Stanley Center of the Broad Institute
- National Institute of Health Research (NIHR)
- NIHR BioResource
- NIHR Cambridge Biomedical Research Centre
- NIHR Blood and Transplant Research Unit in Donor Health and Genomics
- UK MRC [G0800270]
- British Heart Foundation [SP/09/002]
- Center for Inherited Disease Research (CIDR) [1 X01 HG005274-01]
- CIDR from the National Institutes of Health [HHSN268200782096C]
- Collaborative Genetic Study of Nicotine Dependence (COGEND) [P01 CA089392]
- University of Wisconsin Transdisciplinary Tobacco Use Research Center [P50 DA019706, P50 CA084724]
- High-Density SNP Association Analysis of Melanoma: Case-Control and Outcomes Investigation
- National Institutes of Health [R01 EY020483]
- Wellcome Trust Case Control Consortium 2 project [085475/B/08/Z, 085475/Z/08/Z]
- [3P50CA093459]
- [5P50CA097007]
- [5R01ES011740]
- [5R01CA133996]
- Academy of Finland (AKA) [286500, 286500] Funding Source: Academy of Finland (AKA)
- Medical Research Council [MR/L010305/1, MR/K026992/1, G9815508, MR/M008436/1, MC_PC_15018, MR/P005748/1] Funding Source: researchfish
- MRC [MR/P005748/1, G0901310, G0800270, MR/M008436/1] Funding Source: UKRI
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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.
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