Journal
BIOLOGICAL PSYCHIATRY
Volume 85, Issue 7, Pages 554-562Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2018.08.022
Keywords
ARC; Genetics; NMDAR; Schizophrenia; Sequencing; Voltage-gated sodium channels
Categories
Funding
- Medical Research Council Centre [MR/L010305/1, G0800509]
- European Community Seventh Framework Programme [HEALTH-F2-2010-241909]
- European Union Seventh Framework Programme for research, technological development, and demonstration [279227]
- ESRC
- Wellcome
- MRC [MR/N01104X/1]
- Economic and Social Research Council [ES/M001660/1]
- Medical Research Council 58READIE Project [WT095219MA, G1001799]
- Wellcome Trust [076113, 068545/Z/02]
- Medical Research Council [G0000934]
- NIMH [R01MH077139]
- Sylvan C. Herman Foundation
- Stanley Medical Research Institute
- Swedish Research Council [20094959, 2011-4659]
- NIMH Grand Opportunity Grant [RCMH089905]
- Geestkracht programme of the Dutch Health Research Council (Zon-Mw) [10-000-1001]
- Lundbeck
- AstraZeneca
- Eli Lilly
- Janssen Cilag
- Amsterdam: Academic Psychiatric Centre of the Academic Medical Center
- Amsterdam: mental health institution: GGZ Ingeest
- Amsterdam: mental health institution: Arkin
- Amsterdam: mental health institution: Dijk en Duin
- Amsterdam: mental health institution: GGZ Rivierduinen
- Amsterdam: mental health institution: Erasmus Medical Centre
- Amsterdam: mental health institution: GGZ Noord Holland Noord
- Groningen: University Medical Center Groningen
- Groningen: mental health institution: Lentis
- Groningen: mental health institution: GGZ Friesland
- Groningen: mental health institution: GGZ Drenthe
- Groningen: mental health institution: Dimence
- Groningen: mental health institution: Mediant
- Groningen: mental health institution: GGNet Warnsveld
- Groningen: mental health institution: Yulius Dordrecht
- Groningen: mental health institution: Parnassia psycho-medical center The Hague
- Maastricht: Maastricht University Medical Centre
- Maastricht: mental health institution: GGZ Eindhoven en De Kempen
- Maastricht: mental health institution: GGZ Breburg
- Maastricht: mental health institution: GGZ Oost-Brabant
- Maastricht: mental health institution: Vincent van Gogh voor Geestelijke Gezondheid
- Maastricht: mental health institution: Mondriaan
- Maastricht: mental health institution: Virenze riagg
- Maastricht: mental health institution: Zuyderland GGZ
- Maastricht: mental health institution: MET ggz
- Maastricht: mental health institution: Universitair Centrum Sint-Jozef Kortenberg
- Maastricht: mental health institution: CAPRI University of Antwerp
- Maastricht: mental health institution: PC Ziekeren Sint-Truiden
- Maastricht: mental health institution: PZ Sancta Maria Sint-Truiden
- Maastricht: mental health institution: GGZ Overpelt
- Maastricht: mental health institution: OPZ Rekem
- Utrecht: University Medical Center Utrecht
- Utrecht: mental health institution: Altrecht
- Utrecht: mental health institution: GGZ Centraal
- Utrecht: mental health institution: Delta
- ESRC [ES/S008349/1] Funding Source: UKRI
- MRC [MR/N01104X/1, MR/N01104X/2, G1001799, MR/P005748/1, MR/L023784/2, UKDRI-3003] Funding Source: UKRI
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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.
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