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

Rees, Elliott ORCID: https://orcid.org/0000-0002-6168-9222, Carrera, Noa ORCID: https://orcid.org/0000-0003-0739-0382, Morgan, Joanne, Hambridge, Kirsty, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Pocklington, Andrew J. ORCID: https://orcid.org/0000-0002-2137-0452, Richards, Alexander L., Pardinas, Antonio F. ORCID: https://orcid.org/0000-0001-6845-7590, McDonald, Colm, Donohoe, Gary, Morris, Derek W., Kenny, Elaine, Kelleher, Eric, Gill, Michael, Corvin, Aiden, Kirov, George ORCID: https://orcid.org/0000-0002-3427-3950, Walters, James T. R. ORCID: https://orcid.org/0000-0002-6980-4053, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862 and O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379 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:	Professional Services > Advanced Research Computing @ Cardiff (ARCCA) Schools > Medicine Research Institutes & Centres > MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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
URI:	https://orca.cardiff.ac.uk/id/eprint/115504

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