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 ORCID: https://orcid.org/0000-0002-6168-9222, Bergen, Sarah, Hultman, Christina, Kirov, George ORCID: https://orcid.org/0000-0002-3427-3950, O'Donovan, Michael ORCID: https://orcid.org/0000-0001-7073-2379, Owen, Michael ORCID: https://orcid.org/0000-0003-4798-0862, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Sklar, Pamela, Sullivan, Patrick F., Purcell, Shaun M., Crowley, James J. and Ruderfer, Douglas M. 2020. Characterization of single gene copy number variants in schizophrenia. Biological Psychiatry 87 (8) , pp. 736-744. 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:	Publication
Status:	Published
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:	24 Nov 2024 12:45
URI:	https://orca.cardiff.ac.uk/id/eprint/125988

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