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

21 Citations (Web of Science)

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

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10.1016/j.biopsych.2018.08.022

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

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}",

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

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 - Genetics

KW - NMDAR

KW - Schizophrenia

KW - Sequencing

KW - Voltage-gated sodium channels

KW - DE-NOVO MUTATIONS

KW - GENOME-WIDE ASSOCIATION

KW - OF-FUNCTION VARIANTS

KW - RISK

KW - INDIVIDUALS

KW - FRAMEWORK

KW - SUSCEPTIBILITY

KW - DISORDERS

KW - SETD1A

KW - BURDEN

U2 - 10.1016/j.biopsych.2018.08.022

DO - 10.1016/j.biopsych.2018.08.022

M3 - Article

C2 - 30420267

VL - 85

SP - 554

EP - 562

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 7

ER -