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Targeted sequencing of 10,198 samples confirms abnormalities in neuronal activity and implicates voltage-gated sodium channels in schizophrenia pathogenesis

Rees, Elliott, Carrera, Noa, Morgan, Joanne, Hambridge, Kirsty, Escott-Price, Valentina, Pocklington, Andrew J., Richards, Alexander L., Pardinas, Antonio F., McDonald, Colm, Donohoe, Gary, Morris, Derek W., Kenny, Elaine, Kelleher, Eric, Gill, Michael, Corvin, Aiden, Kirov, George, Walters, James T. R., Holmans, Peter, Owen, Michael J. and O'Donovan, Michael C. 2019. Targeted sequencing of 10,198 samples confirms abnormalities in neuronal activity and implicates voltage-gated sodium channels in schizophrenia pathogenesis. Biological Psychiatry 85 (7) , pp. 554-562. 10.1016/j.biopsych.2018.08.022

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Abstract

Background Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms. Methods We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5,207 cases and 4,991 controls. Included among these genes were members of ARC and NMDAR post-synaptic protein complexes, as well as voltage-gated sodium and calcium channels. We performed a rare variant meta-analysis with published sequencing data for a total of 11,319 cases, 15,854 controls and 1,136 trios. Results While no individual gene was significantly associated with schizophrenia after genome-wide correction for multiple testing, we strengthen the evidence that rare exonic variants in the synaptic complexes ARC (P = 4.0 x 10-4) and NMDAR (P = 1.7 x 10-5) are risk factors for schizophrenia. In addition, we found that LoF variants and missense variants at paralog conserved sites were enriched in voltage-gated sodium channels, particularly the alpha subunits (P = 8.6 x 10-4). Conclusions In one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis and confirm the involvement of ARC and NMDAR post-synaptic complexes.

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: 4 October 2018
Date of Acceptance: 31 August 2018
Last Modified: 15 Mar 2019 09:41
URI: http://orca.cf.ac.uk/id/eprint/115504

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