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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 ORCID:, Carrera, Noa ORCID:, Morgan, Joanne, Hambridge, Kirsty, Escott-Price, Valentina ORCID:, Pocklington, Andrew J. ORCID:, Richards, Alexander L., Pardinas, Antonio F. ORCID:, McDonald, Colm, Donohoe, Gary, Morris, Derek W., Kenny, Elaine, Kelleher, Eric, Gill, Michael, Corvin, Aiden, Kirov, George ORCID:, Walters, James T. R. ORCID:, Holmans, Peter ORCID:, Owen, Michael J. ORCID: and O'Donovan, Michael C. ORCID: 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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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: Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: This is an open access article under the CC BY license (
Publisher: Elsevier
ISSN: 0006-3223
Date of First Compliant Deposit: 4 October 2018
Date of Acceptance: 31 August 2018
Last Modified: 12 Oct 2023 04:43

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