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Characterization of single gene copy number variants in schizophrenia

Szatkiewicz, Jin P., Fromer, Menachem, Nonneman, Randal J., Ancalade, NaEshia, Johnson, Jessica S., Stahl, Eli A., Rees, Elliott, Bergen, Sarah, Hultman, Christina, Kirov, George, O'Donovan, Michael, Owen, Michael, Holmans, Peter, Sklar, Pamela, Sullivan, Patrick F., Purcell, Shaun M., Crowley, James J. and Ruderfer, Douglas M. 2019. Characterization of single gene copy number variants in schizophrenia. Biological Psychiatry 10.1016/j.biopsych.2019.09.023
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Abstract

Background Genetic studies of schizophrenia have implicated numerous risk loci including several copy number variants (CNVs) of large effect and hundreds of loci of small effect. In only a few cases has a specific gene been clearly identified. Rare CNVs affecting a single gene offer a potential avenue to discovering schizophrenia risk genes. Methods CNVs were generated from exome-sequencing of 4,913 schizophrenia cases and 6,188 controls from Sweden. We integrated multiple CNV calling methods (XHMM and ExomeDepth) to expand our set of single-gene CNVs and leveraged two different approaches for validating these variants (qPCR and Nanostring). Results We found a significant excess of all rare CNVs (deletions p=0.0004, duplications p=0.0006) and single-gene CNVs (deletions p=0.04, duplications p=0.03) in schizophrenia cases compared to controls. An expanded set of CNVs generated from integrating multiple approaches showed a significant burden of deletions in 11/21 gene-sets previously implicated in schizophrenia and across all genes in those sets (p=0.008), although no tests survived correction. We performed an extensive validation of all deletions in the significant set of voltage-gated calcium channels among CNVs called from both exome-sequencing and genotyping arrays. In total, 4 exonic, single-gene deletions validated in cases and none in controls (p=0.039), of which all were identified by exome-sequencing. Conclusions These results point to the potential contribution of single-gene CNVs to schizophrenia, that the utility of exome-sequencing for CNV calling has yet to be maximized and single-gene CNVs should be included in gene focused studies using other classes of variation.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Elsevier
ISSN: 0006-3223
Date of First Compliant Deposit: 11 October 2019
Date of Acceptance: 25 September 2019
Last Modified: 18 Oct 2019 00:23
URI: http://orca-mwe.cf.ac.uk/id/eprint/125988

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