PMID- 30420267
OWN - NLM
STAT- In-Data-Review
LR  - 20190403
IS  - 1873-2402 (Electronic)
IS  - 0006-3223 (Linking)
VI  - 85
IP  - 7
DP  - 2019 Apr 1
TI  - Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity
      and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis.
PG  - 554-562
LID - S0006-3223(18)31878-X [pii]
LID - 10.1016/j.biopsych.2018.08.022 [doi]
AB  - 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.
CI  - Copyright (c) 2018 Society of Biological Psychiatry. Published by Elsevier Inc.
      All rights reserved.
FAU - Rees, Elliott
AU  - Rees E
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University,
      Cardiff, United Kingdom.
FAU - Carrera, Noa
AU  - Carrera N
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University,
      Cardiff, United Kingdom.
FAU - Morgan, Joanne
AU  - Morgan J
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University,
      Cardiff, United Kingdom.
FAU - Hambridge, Kirsty
AU  - Hambridge K
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University,
      Cardiff, United Kingdom.
FAU - Escott-Price, Valentina
AU  - Escott-Price V
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University,
      Cardiff, United Kingdom.
FAU - Pocklington, Andrew J
AU  - Pocklington AJ
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University,
      Cardiff, United Kingdom.
FAU - Richards, Alexander L
AU  - Richards AL
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University,
      Cardiff, United Kingdom.
FAU - Pardinas, Antonio F
AU  - Pardinas AF
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University,
      Cardiff, United Kingdom.
CN  - GROUP Investigators
FAU - McDonald, Colm
AU  - McDonald C
AD  - Centre for Neuroimaging and Cognitive Genomics, National University of Ireland
      Galway, Galway, Ireland.
FAU - Donohoe, Gary
AU  - Donohoe G
AD  - Centre for Neuroimaging and Cognitive Genomics, National University of Ireland
      Galway, Galway, Ireland.
FAU - Morris, Derek W
AU  - Morris DW
AD  - Centre for Neuroimaging and Cognitive Genomics, National University of Ireland
      Galway, Galway, Ireland.
FAU - Kenny, Elaine
AU  - Kenny E
AD  - Department of Psychiatry and Trinity Translational Medicine Institute, Trinity
      College Dublin, Dublin, Ireland.
FAU - Kelleher, Eric
AU  - Kelleher E
AD  - Department of Psychiatry and Trinity Translational Medicine Institute, Trinity
      College Dublin, Dublin, Ireland.
FAU - Gill, Michael
AU  - Gill M
AD  - Department of Psychiatry and Trinity Translational Medicine Institute, Trinity
      College Dublin, Dublin, Ireland.
FAU - Corvin, Aiden
AU  - Corvin A
AD  - Department of Psychiatry and Trinity Translational Medicine Institute, Trinity
      College Dublin, Dublin, Ireland.
FAU - Kirov, George
AU  - Kirov G
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University,
      Cardiff, United Kingdom.
FAU - Walters, James T R
AU  - Walters JTR
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University,
      Cardiff, United Kingdom.
FAU - Holmans, Peter
AU  - Holmans P
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University,
      Cardiff, United Kingdom.
FAU - Owen, Michael J
AU  - Owen MJ
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University,
      Cardiff, United Kingdom. Electronic address: owenmj@cardiff.ac.uk.
FAU - O'Donovan, Michael C
AU  - O'Donovan MC
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University,
      Cardiff, United Kingdom. Electronic address: odonovanmc@cardiff.ac.uk.
LA  - eng
GR  - Wellcome Trust/United Kingdom
GR  - MR/L010305/1/Medical Research Council/United Kingdom
GR  - R01 MH077139/MH/NIMH NIH HHS/United States
PT  - Journal Article
DEP - 20181001
PL  - United States
TA  - Biol Psychiatry
JT  - Biological psychiatry
JID - 0213264
PMC - PMC6428681
OTO - NOTNLM
OT  - ARC
OT  - Genetics
OT  - NMDAR
OT  - Schizophrenia
OT  - Sequencing
OT  - Voltage-gated sodium channels
IR  - Alizadeh BZ
FIR - Alizadeh, Behrooz Z
IR  - van Amelsvoort T
FIR - van Amelsvoort, Therese
IR  - Bartels-Velthuis AA
FIR - Bartels-Velthuis, Agna A
IR  - van Beveren NJ
FIR - van Beveren, Nico J
IR  - Bruggeman R
FIR - Bruggeman, Richard
IR  - Cahn W
FIR - Cahn, Wiepke
IR  - de Haan L
FIR - de Haan, Lieuwe
IR  - Delespaul P
FIR - Delespaul, Philippe
IR  - Meijer CJ
FIR - Meijer, Carin J
IR  - Myin-Germeys I
FIR - Myin-Germeys, Inez
IR  - Kahn RS
FIR - Kahn, Rene S
IR  - Schirmbeck F
FIR - Schirmbeck, Frederike
IR  - Simons CJP
FIR - Simons, Claudia J P
IR  - van Haren NE
FIR - van Haren, Neeltje E
IR  - van Os J
FIR - van Os, Jim
IR  - van Winkel R
FIR - van Winkel, Ruud
IR  - Luykx JJ
FIR - Luykx, Jurjen J
EDAT- 2018/11/14 06:00
MHDA- 2018/11/14 06:00
CRDT- 2018/11/14 06:00
PHST- 2018/04/09 00:00 [received]
PHST- 2018/08/31 00:00 [revised]
PHST- 2018/08/31 00:00 [accepted]
PHST- 2018/11/14 06:00 [pubmed]
PHST- 2018/11/14 06:00 [medline]
PHST- 2018/11/14 06:00 [entrez]
AID - S0006-3223(18)31878-X [pii]
AID - 10.1016/j.biopsych.2018.08.022 [doi]
PST - ppublish
SO  - Biol Psychiatry. 2019 Apr 1;85(7):554-562. doi: 10.1016/j.biopsych.2018.08.022.
      Epub 2018 Oct 1.