Peer-Reviewed Journal Details
Mandatory Fields
Rees, E;Carrera, N;Morgan, J;Hambridge, K;Escott-Price, V;Pocklington, AJ;Richards, AL;Pardinas, AF;McDonald, C;Donohoe, G;Morris, DW;Kenny, E;Kelleher, E;Gill, M;Corvin, A;Kirov, G;Walters, JTR;Holmans, P;Owen, MJ;O'Donovan, MC;Alizadeh, BZ;van Amelsvoort, T;Bartels-Velthuis, AA;van Beveren, NJ;Bruggeman, R;Cahn, W;de Haan, L;Delespaul, P;Meijer, CJ;Myin-Germeys, I;Kahn, RS;Schirmbeck, F;Simons, CJP;van Haren, NE;van Os, J;van Winkel, R;Luykx, JJ
2019
April
Biological Psychiatry
Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis
Published
Optional Fields
DE-NOVO MUTATIONS GENOME-WIDE ASSOCIATION OF-FUNCTION VARIANTS RISK INDIVIDUALS FRAMEWORK SUSCEPTIBILITY DISORDERS SETD1A BURDEN
85
554
562
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.
0006-3223
10.1016/j.biopsych.2018.08.022
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