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Exome arrays capture polygenic rare variant contributions to schizophrenia

Richards, Alexander, Leonenko, Ganna M, Walters, James Tynan Rhys, Kavanagh, D, Rees, Elliott, Evans, Anna, Chambert, K. D., Moran, J. L., Goldstein, J., Neale, B. M., McCarroll, S. A., Pocklington, Andrew, Holmans, Peter Alan, Owen, Michael John and O'Donovan, Michael Conlon 2016. Exome arrays capture polygenic rare variant contributions to schizophrenia. Human Molecular Genetics 25 (5) , pp. 1001-1007. 10.1093/hmg/ddv620

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Schizophrenia is a highly heritable disorder. Genome-wide association studies based largely on common alleles have identified over 100 schizophrenia risk loci but it is also evident from studies of copy number variants and from exome sequencing studies that rare alleles are also involved. Full characterization of the contribution of rare alleles to the disorder awaits the deployment of sequencing technology in very large sample sizes, meanwhile, as an interim measure, exome arrays allow rare non-synonymous variants to be sampled at a fraction of the cost. In an analysis of exome array data from 13,688 individuals (5585 cases and 8103 controls) from the UK, we found that rare (MAF<0.1%) variant association signal was enriched among genes that map to autosomal loci that are genome-wide significant in common variant studies of schizophrenia (PGWAS=0.01) as well as gene sets known to be enriched for rare variants in sequencing studies (PRARE=0.026). We also identified the gene-wise equivalent of genome-wide significant support for WDR88 (WD repeat-containing protein 88), a gene of unknown function (P =6.5x10-7). Rare alleles represented on exome chip arrays contribute to the genetic architecture of schizophrenia, but as is the case for GWAS, very large studies are required to reveal additional susceptibility alleles for the disorder.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > R Medicine (General)
Publisher: Oxford University Press
ISSN: 0964-6906
Funders: MRC
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 21 December 2015
Last Modified: 15 Oct 2020 01:30

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