Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis.
Adult
Cohort Studies
Cytoskeletal Proteins
/ genetics
Humans
Ireland
Middle Aged
Nerve Tissue Proteins
/ genetics
Netherlands
Neurons
/ physiology
Receptors, N-Methyl-D-Aspartate
/ genetics
Risk Factors
Schizophrenia
/ genetics
Sequence Analysis, DNA
United Kingdom
Voltage-Gated Sodium Channels
/ genetics
ARC
Genetics
NMDAR
Schizophrenia
Sequencing
Voltage-gated sodium channels
Journal
Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264
Informations de publication
Date de publication:
01 04 2019
01 04 2019
Historique:
received:
09
04
2018
revised:
31
08
2018
accepted:
31
08
2018
pubmed:
14
11
2018
medline:
30
1
2020
entrez:
14
11
2018
Statut:
ppublish
Résumé
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. 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. 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 × 10 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.
Sections du résumé
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 × 10
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.
Identifiants
pubmed: 30420267
pii: S0006-3223(18)31878-X
doi: 10.1016/j.biopsych.2018.08.022
pmc: PMC6428681
pii:
doi:
Substances chimiques
Cytoskeletal Proteins
0
Nerve Tissue Proteins
0
Receptors, N-Methyl-D-Aspartate
0
Voltage-Gated Sodium Channels
0
activity regulated cytoskeletal-associated protein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
554-562Subventions
Organisme : NIMH NIH HHS
ID : R01 MH077139
Pays : United States
Organisme : Medical Research Council
ID : MR/P005748/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L023784/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L010305/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N01104X/2
Pays : United Kingdom
Investigateurs
Behrooz Z Alizadeh
(BZ)
Therese van Amelsvoort
(T)
Agna A Bartels-Velthuis
(AA)
Nico J van Beveren
(NJ)
Richard Bruggeman
(R)
Wiepke Cahn
(W)
Lieuwe de Haan
(L)
Philippe Delespaul
(P)
Carin J Meijer
(CJ)
Inez Myin-Germeys
(I)
Rene S Kahn
(RS)
Frederike Schirmbeck
(F)
Claudia J P Simons
(CJP)
Neeltje E van Haren
(NE)
Jim van Os
(J)
Ruud van Winkel
(R)
Jurjen J Luykx
(JJ)
Informations de copyright
Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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