Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis

Elliott Rees, Noa Carrera, Joanne Morgan, Kirsty Hambridge, Valentina Escott-Price, Andrew J. Pocklington, Alexander L. Richards, Antonio F. Pardinas, Colm McDonald, Gary Donohoe, Derek W. Morris, Elaine Kenny, Eric Kelleher, Michael Gill, Aiden Corvin, George Kirov, James T. R. Walters, Peter Holmans, Michael J. Owen*, Michael C. O'Donovan*Behrooz Z. Alizadeh, Therese van Amelsvoort, Agna A. Bartels-Velthuis, Nico J. van Beveren, Richard Bruggeman, Wiepke Cahn, Lieuwe de Haan, Philippe Delespaul, Carin J. Meijer, Inez Myin-Germeys, Rene S. Kahn, Frederike Schirmbeck, Claudia J. P. Simons, Neeltje E. van Haren, Jim van Os, Ruud van Winkel, Jurjen J. Luykx, GRP Investigators

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

21 Citations (Web of Science)


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 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic 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 1136 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 ARC (p = 4.0 x 10(-4)) and NMDAR (p = 1.7 x 10(-5)) synaptic complexes are risk factors for schizophrenia. In addition, we found that loss-of-function 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 postsynaptic complexes.

Original languageEnglish
Pages (from-to)554-562
Number of pages9
JournalBiological Psychiatry
Issue number7
Publication statusPublished - 1 Apr 2019


  • ARC
  • Genetics
  • Schizophrenia
  • Sequencing
  • Voltage-gated sodium channels
  • RISK
  • SETD1A

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