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

doi:10.1016/j.biopsych.2018.08.022

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 journal › Article › Academic › peer-review

Abstract

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 language	English
Pages (from-to)	554-562
Number of pages	9
Journal	Biological Psychiatry
Volume	85
Issue number	7
DOIs	https://doi.org/10.1016/j.biopsych.2018.08.022
Publication status	Published - 1 Apr 2019

Keywords

ARC
BURDEN
DE-NOVO MUTATIONS
DISORDERS
FRAMEWORK
GENOME-WIDE ASSOCIATION
Genetics
INDIVIDUALS
NMDAR
OF-FUNCTION VARIANTS
RISK
SETD1A
SUSCEPTIBILITY
Schizophrenia
Sequencing
Voltage-gated sodium channels

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Rees, E., Carrera, N., Morgan, J., Hambridge, K., Escott-Price, V., Pocklington, A. J., Richards, A. L., Pardinas, A. F., McDonald, C., Donohoe, G., Morris, D. W., Kenny, E., Kelleher, E., Gill, M., Corvin, A., Kirov, G., Walters, J. T. R., Holmans, P., Owen, M. J., ... GRP Investigators (2019). Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis. Biological Psychiatry, 85(7), 554-562. https://doi.org/10.1016/j.biopsych.2018.08.022

@article{ecf6774331c64849b7bd98c8c9e6d27f,

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

abstract = "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.",

keywords = "ARC, BURDEN, DE-NOVO MUTATIONS, DISORDERS, FRAMEWORK, GENOME-WIDE ASSOCIATION, Genetics, INDIVIDUALS, NMDAR, OF-FUNCTION VARIANTS, RISK, SETD1A, SUSCEPTIBILITY, Schizophrenia, Sequencing, Voltage-gated sodium channels",

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

note = "Funding Information: Data governance was provided by the METADAC data access committee, funded by ESRC , Wellcome , and MRC . (Grant No. MR/N01104X/1 ). This work made use of data and samples generated by the 1958 Birth Cohort (NCDS), which is managed by the Centre for Longitudinal Studies at the UCL Institute of Education, funded by the Economic and Social Research Council (Grant No. ES/M001660/1 ). Access to these resources was enabled via the Wellcome Trust and Medical Research Council 58READIE Project (Grant Nos. WT095219MA and G1001799). Genotyping was undertaken as part of the Wellcome Trust Case Control Consortium under Wellcome Trust award 076113, and a full list of the investigators who contributed to the generation of the data is available at www.wtccc.org.uk . Before 2015 biomedical resources were maintained under the Wellcome Trust and Medical Research Council 58READIE Project (Grant Nos. WT095219MA and G1001799). This work made use of data and samples generated by the 1958 Birth Cohort ( http://www2.le.ac.uk/projects/birthcohort , http://www.bristol.ac.uk/alspac/ , http://www.cls.ioe.ac.uk/ncds , http://www.esds.ac.uk/findingData/ncds.asp ) under Grant No. G0000934 from the Medical Research Council, and Grant No. 068545/Z/02 from the Wellcome Trust. Funding Information: The work at Cardiff University was supported by Medical Research Council Centre Grant No. MR/L010305/1 (to MJO) and Program Grant No. G0800509 (to MJO, MCO, JTRW, VE-P, PH, AJP), European Community Seventh Framework Programme Grant No. HEALTH-F2-2010-241909 (Project EU-GEI), and European Union Seventh Framework Programme for research, technological development, and demonstration Grant No. 279227 (CRESTAR Consortium).Data governance was provided by the METADAC data access committee, funded by ESRC, Wellcome, and MRC. (Grant No. MR/N01104X/1). This work made use of data and samples generated by the 1958 Birth Cohort (NCDS), which is managed by the Centre for Longitudinal Studies at the UCL Institute of Education, funded by the Economic and Social Research Council (Grant No. ES/M001660/1). Access to these resources was enabled via the Wellcome Trust and Medical Research Council 58READIE Project (Grant Nos. WT095219MA and G1001799). Genotyping was undertaken as part of the Wellcome Trust Case Control Consortium under Wellcome Trust award 076113, and a full list of the investigators who contributed to the generation of the data is available at www.wtccc.org.uk. Before 2015 biomedical resources were maintained under the Wellcome Trust and Medical Research Council 58READIE Project (Grant Nos. WT095219MA and G1001799). This work made use of data and samples generated by the 1958 Birth Cohort (http://www2.le.ac.uk/projects/birthcohort, http://www.bristol.ac.uk/alspac/, http://www.cls.ioe.ac.uk/ncds, http://www.esds.ac.uk/findingData/ncds.asp) under Grant No. G0000934 from the Medical Research Council, and Grant No. 068545/Z/02 from the Wellcome Trust.The datasets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000473.v2.p2. Samples used for data analysis were provided by the Swedish Cohort Collection supported by the NIMH Grant No. R01MH077139, the Sylvan C. Herman Foundation, the Stanley Medical Research Institute and The Swedish Research Council (Grant Nos. 2009-4959 and 2011-4659). Support for the exome sequencing was provided by the NIMH Grand Opportunity Grant No. RCMH089905, the Sylvan C. Herman Foundation, a grant from the Stanley Medical Research Institute and multiple gifts to the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. Funding Information: The datasets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000473.v2.p2. Samples used for data analysis were provided by the Swedish Cohort Collection supported by the NIMH Grant No. R01MH077139, the Sylvan C. Herman Foundation, the Stanley Medical Research Institute and The Swedish Research Council (Grant Nos. 2009-4959 and 2011-4659). Support for the exome sequencing was provided by the NIMH Grand Opportunity Grant No. RCMH089905, the Sylvan C. Herman Foundation, a grant from the Stanley Medical Research Institute and multiple gifts to the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. Funding Information: The infrastructure for the GROUP study is funded through the Geestkracht programme of the Dutch Health Research Council (Zon-Mw, Grant No. 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental health care organizations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Groningen: University Medical Center Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psycho-medical center The Hague. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en De Kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Utrecht: University Medical Center Utrecht and the mental health institutions Altrecht, GGZ Centraal and Delta.) Funding Information: This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk . Funding for the project was provided by the Wellcome Trust. Those who carried out the original DECIPHER analysis and collection of the Data bear no responsibility for the further analysis or interpretation of it by the Recipient or its Registered Users. Funding Information: The datasets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000473.v2.p2. Samples used for data analysis were provided by the Swedish Cohort Collection supported by the NIMH Grant No. R01MH077139 , the Sylvan C. Herman Foundation , the Stanley Medical Research Institute and The Swedish Research Council (Grant Nos. 2009-4959 and 2011-4659 ). Support for the exome sequencing was provided by the NIMH Grand Opportunity Grant No. RCMH089905 , the Sylvan C. Herman Foundation, a grant from the Stanley Medical Research Institute and multiple gifts to the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. Funding Information: The work at Cardiff University was supported by Medical Research Council Centre Grant No. MR/L010305/1 (to MJO) and Program Grant No. G0800509 (to MJO, MCO, JTRW, VE-P, PH, AJP), European Community Seventh Framework Programme Grant No. HEALTH-F2-2010-241909 (Project EU-GEI), and European Union Seventh Framework Programme for research, technological development, and demonstration Grant No. 279227 (CRESTAR Consortium). Publisher Copyright: {\textcopyright} 2018 Society of Biological Psychiatry",

year = "2019",

month = apr,

day = "1",

doi = "10.1016/j.biopsych.2018.08.022",

language = "English",

volume = "85",

pages = "554--562",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier Science",

number = "7",

}

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 & GRP Investigators 2019, 'Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis', Biological Psychiatry, vol. 85, no. 7, pp. 554-562. https://doi.org/10.1016/j.biopsych.2018.08.022

TY - JOUR

T1 - Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis

AU - Rees, Elliott

AU - Carrera, Noa

AU - Morgan, Joanne

AU - Hambridge, Kirsty

AU - Escott-Price, Valentina

AU - Pocklington, Andrew J.

AU - Richards, Alexander L.

AU - Pardinas, Antonio F.

AU - McDonald, Colm

AU - Donohoe, Gary

AU - Morris, Derek W.

AU - Kenny, Elaine

AU - Kelleher, Eric

AU - Gill, Michael

AU - Corvin, Aiden

AU - Kirov, George

AU - Walters, James T. R.

AU - Holmans, Peter

AU - Owen, Michael J.

AU - O'Donovan, Michael C.

AU - Alizadeh, Behrooz Z.

AU - van Amelsvoort, Therese

AU - Bartels-Velthuis, Agna A.

AU - van Beveren, Nico J.

AU - Bruggeman, Richard

AU - Cahn, Wiepke

AU - de Haan, Lieuwe

AU - Delespaul, Philippe

AU - Meijer, Carin J.

AU - Myin-Germeys, Inez

AU - Kahn, Rene S.

AU - Schirmbeck, Frederike

AU - Simons, Claudia J. P.

AU - van Haren, Neeltje E.

AU - van Os, Jim

AU - van Winkel, Ruud

AU - Luykx, Jurjen J.

AU - GRP Investigators

N1 - Funding Information: Data governance was provided by the METADAC data access committee, funded by ESRC , Wellcome , and MRC . (Grant No. MR/N01104X/1 ). This work made use of data and samples generated by the 1958 Birth Cohort (NCDS), which is managed by the Centre for Longitudinal Studies at the UCL Institute of Education, funded by the Economic and Social Research Council (Grant No. ES/M001660/1 ). Access to these resources was enabled via the Wellcome Trust and Medical Research Council 58READIE Project (Grant Nos. WT095219MA and G1001799). Genotyping was undertaken as part of the Wellcome Trust Case Control Consortium under Wellcome Trust award 076113, and a full list of the investigators who contributed to the generation of the data is available at www.wtccc.org.uk . Before 2015 biomedical resources were maintained under the Wellcome Trust and Medical Research Council 58READIE Project (Grant Nos. WT095219MA and G1001799). This work made use of data and samples generated by the 1958 Birth Cohort ( http://www2.le.ac.uk/projects/birthcohort , http://www.bristol.ac.uk/alspac/ , http://www.cls.ioe.ac.uk/ncds , http://www.esds.ac.uk/findingData/ncds.asp ) under Grant No. G0000934 from the Medical Research Council, and Grant No. 068545/Z/02 from the Wellcome Trust. Funding Information: The work at Cardiff University was supported by Medical Research Council Centre Grant No. MR/L010305/1 (to MJO) and Program Grant No. G0800509 (to MJO, MCO, JTRW, VE-P, PH, AJP), European Community Seventh Framework Programme Grant No. HEALTH-F2-2010-241909 (Project EU-GEI), and European Union Seventh Framework Programme for research, technological development, and demonstration Grant No. 279227 (CRESTAR Consortium).Data governance was provided by the METADAC data access committee, funded by ESRC, Wellcome, and MRC. (Grant No. MR/N01104X/1). This work made use of data and samples generated by the 1958 Birth Cohort (NCDS), which is managed by the Centre for Longitudinal Studies at the UCL Institute of Education, funded by the Economic and Social Research Council (Grant No. ES/M001660/1). Access to these resources was enabled via the Wellcome Trust and Medical Research Council 58READIE Project (Grant Nos. WT095219MA and G1001799). Genotyping was undertaken as part of the Wellcome Trust Case Control Consortium under Wellcome Trust award 076113, and a full list of the investigators who contributed to the generation of the data is available at www.wtccc.org.uk. Before 2015 biomedical resources were maintained under the Wellcome Trust and Medical Research Council 58READIE Project (Grant Nos. WT095219MA and G1001799). This work made use of data and samples generated by the 1958 Birth Cohort (http://www2.le.ac.uk/projects/birthcohort, http://www.bristol.ac.uk/alspac/, http://www.cls.ioe.ac.uk/ncds, http://www.esds.ac.uk/findingData/ncds.asp) under Grant No. G0000934 from the Medical Research Council, and Grant No. 068545/Z/02 from the Wellcome Trust.The datasets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000473.v2.p2. Samples used for data analysis were provided by the Swedish Cohort Collection supported by the NIMH Grant No. R01MH077139, the Sylvan C. Herman Foundation, the Stanley Medical Research Institute and The Swedish Research Council (Grant Nos. 2009-4959 and 2011-4659). Support for the exome sequencing was provided by the NIMH Grand Opportunity Grant No. RCMH089905, the Sylvan C. Herman Foundation, a grant from the Stanley Medical Research Institute and multiple gifts to the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. Funding Information: The datasets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000473.v2.p2. Samples used for data analysis were provided by the Swedish Cohort Collection supported by the NIMH Grant No. R01MH077139, the Sylvan C. Herman Foundation, the Stanley Medical Research Institute and The Swedish Research Council (Grant Nos. 2009-4959 and 2011-4659). Support for the exome sequencing was provided by the NIMH Grand Opportunity Grant No. RCMH089905, the Sylvan C. Herman Foundation, a grant from the Stanley Medical Research Institute and multiple gifts to the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. Funding Information: The infrastructure for the GROUP study is funded through the Geestkracht programme of the Dutch Health Research Council (Zon-Mw, Grant No. 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental health care organizations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Groningen: University Medical Center Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psycho-medical center The Hague. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en De Kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Utrecht: University Medical Center Utrecht and the mental health institutions Altrecht, GGZ Centraal and Delta.) Funding Information: This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk . Funding for the project was provided by the Wellcome Trust. Those who carried out the original DECIPHER analysis and collection of the Data bear no responsibility for the further analysis or interpretation of it by the Recipient or its Registered Users. Funding Information: The datasets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000473.v2.p2. Samples used for data analysis were provided by the Swedish Cohort Collection supported by the NIMH Grant No. R01MH077139 , the Sylvan C. Herman Foundation , the Stanley Medical Research Institute and The Swedish Research Council (Grant Nos. 2009-4959 and 2011-4659 ). Support for the exome sequencing was provided by the NIMH Grand Opportunity Grant No. RCMH089905 , the Sylvan C. Herman Foundation, a grant from the Stanley Medical Research Institute and multiple gifts to the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. Funding Information: The work at Cardiff University was supported by Medical Research Council Centre Grant No. MR/L010305/1 (to MJO) and Program Grant No. G0800509 (to MJO, MCO, JTRW, VE-P, PH, AJP), European Community Seventh Framework Programme Grant No. HEALTH-F2-2010-241909 (Project EU-GEI), and European Union Seventh Framework Programme for research, technological development, and demonstration Grant No. 279227 (CRESTAR Consortium). Publisher Copyright: © 2018 Society of Biological Psychiatry

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

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.

KW - ARC

KW - BURDEN

KW - DE-NOVO MUTATIONS

KW - DISORDERS

KW - FRAMEWORK

KW - GENOME-WIDE ASSOCIATION

KW - Genetics

KW - INDIVIDUALS

KW - NMDAR

KW - OF-FUNCTION VARIANTS

KW - RISK

KW - SETD1A

KW - SUSCEPTIBILITY

KW - Schizophrenia

KW - Sequencing

KW - Voltage-gated sodium channels

U2 - 10.1016/j.biopsych.2018.08.022

DO - 10.1016/j.biopsych.2018.08.022

M3 - Article

C2 - 30420267

SN - 0006-3223

VL - 85

SP - 554

EP - 562

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 7

ER -