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Identification of putative second genetic hits in schizophrenia carriers of high-risk copy number variants and resequencing in additional samples

Rodríguez-López, Julio, Sobrino, Beatriz, Amigo, Jorge, Carrera, Noa, Brenlla, Julio, Agra, Santiago, Paz, Eduardo, Carracedo, Ángel, Páramo, Mario, Arrojo, Manuel and Costas, Javier 2018. Identification of putative second genetic hits in schizophrenia carriers of high-risk copy number variants and resequencing in additional samples. European Archives of Psychiatry and Clinical Neuroscience 268 (6) , pp. 585-592. 10.1007/s00406-017-0799-5

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Abstract

Copy number variants (CNVs) conferring risk of schizophrenia present incomplete penetrance, suggesting the existence of second genetic hits. Identification of second hits may help to find genes with rare variants of susceptibility to schizophrenia. The aim of this work was to search for second hits of moderate/high risk in schizophrenia carriers of risk CNVs and resequencing of the relevant genes in additional samples. To this end, ten patients with risk CNVs at cytobands 15q11.2, 15q11.2-13.1, 16p11.2, or 16p13.11, were subjected to whole-exome sequencing. Rare single nucleotide variants, defined as those absent from main public databases, were classified according to bioinformatic prediction of pathogenicity by CADD scores. The average number of rare predicted pathogenic variants per sample was 13.6 (SD 2.01). Two genes, BFAR and SYNJ1, presented rare predicted pathogenic variants in more than one sample. Follow-up resequencing of these genes in 432 additional cases and 432 controls identified a significant excess of rare predicted pathogenic variants in case samples at SYNJ1. Taking into account its function in clathrin-mediated synaptic vesicle endocytosis at presynaptic terminals, our results suggest an impairment of this process in schizophrenia.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Publisher: Springer
ISSN: 0940-1334
Date of First Compliant Deposit: 28 February 2018
Date of Acceptance: 18 April 2017
Last Modified: 04 Oct 2018 13:59
URI: http://orca-mwe.cf.ac.uk/id/eprint/109624

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