De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia

G. Kirov, A. J. Pocklington, P. Holmans, D. Ivanov, Masashi Ikeda, D. Ruderfer, J. Moran, K. Chambert, D. Toncheva, L. Georgieva, D. Grozeva, M. Fjodorova, R. Wollerton, E. Rees, I. Nikolov, L. N. Van De Lagemaat, A. Bayés, E. Fernandez, P. I. Olason, Y. BöttcherN. H. Komiyama, M. O. Collins, J. Choudhary, K. Stefansson, H. Stefansson, S. G.N. Grant, S. Purcell, P. Sklar, M. C. O'Donovan, M. J. Owen

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Abstract

A small number of rare, recurrent genomic copy number variants (CNVs) are known to substantially increase susceptibility to schizophrenia. As a consequence of the low fecundity in people with schizophrenia and other neurodevelopmental phenotypes to which these CNVs contribute, CNVs with large effects on risk are likely to be rapidly removed from the population by natural selection. Accordingly, such CNVs must frequently occur as recurrent de novo mutations. In a sample of 662 schizophrenia proband-parent trios, we found that rare de novo CNV mutations were significantly more frequent in cases (5.1% all cases, 5.5% family history negative) compared with 2.2% among 2623 controls, confirming the involvement of de novo CNVs in the pathogenesis of schizophrenia. Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2). De novo CNVs of known pathogenic significance in other genomic disorders were also observed, including deletion at the TAR (thrombocytopenia absent radius) region on 1q21.1 and duplication at the WBS (Williams-Beuren syndrome) region at 7q11.23. Multiple de novos spanned genes encoding members of the DLG (discs large) family of membrane-associated guanylate kinases (MAGUKs) that are components of the postsynaptic density (PSD). Two de novos also affected EHMT1, a histone methyl transferase known to directly regulate DLG family members. Using a systems biology approach and merging novel CNV and proteomics data sets, systematic analysis of synaptic protein complexes showed that, compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 × 10 -6). This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 × 10 -6) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 × 10 -8) postsynaptic signalling complexes. In an analysis of 18 492 subjects (7907 cases and 10 585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14). Our data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia.

Original languageEnglish
Pages (from-to)142-153
Number of pages12
JournalMolecular Psychiatry
Volume17
Issue number2
DOIs
Publication statusPublished - 01-02-2012

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Schizophrenia
N-Methyl-D-Aspartate Receptors
Cytoskeleton
Post-Synaptic Density
Proteins
Guanylate Kinases
Mutation
Neuronal Plasticity
Systems Biology
Genetic Selection
Proteome
Transferases
Proteomics
Histones
Cognition
Fertility
Phenotype
Population
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Kirov, G. ; Pocklington, A. J. ; Holmans, P. ; Ivanov, D. ; Ikeda, Masashi ; Ruderfer, D. ; Moran, J. ; Chambert, K. ; Toncheva, D. ; Georgieva, L. ; Grozeva, D. ; Fjodorova, M. ; Wollerton, R. ; Rees, E. ; Nikolov, I. ; Van De Lagemaat, L. N. ; Bayés, A. ; Fernandez, E. ; Olason, P. I. ; Böttcher, Y. ; Komiyama, N. H. ; Collins, M. O. ; Choudhary, J. ; Stefansson, K. ; Stefansson, H. ; Grant, S. G.N. ; Purcell, S. ; Sklar, P. ; O'Donovan, M. C. ; Owen, M. J. / De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. In: Molecular Psychiatry. 2012 ; Vol. 17, No. 2. pp. 142-153.
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abstract = "A small number of rare, recurrent genomic copy number variants (CNVs) are known to substantially increase susceptibility to schizophrenia. As a consequence of the low fecundity in people with schizophrenia and other neurodevelopmental phenotypes to which these CNVs contribute, CNVs with large effects on risk are likely to be rapidly removed from the population by natural selection. Accordingly, such CNVs must frequently occur as recurrent de novo mutations. In a sample of 662 schizophrenia proband-parent trios, we found that rare de novo CNV mutations were significantly more frequent in cases (5.1{\%} all cases, 5.5{\%} family history negative) compared with 2.2{\%} among 2623 controls, confirming the involvement of de novo CNVs in the pathogenesis of schizophrenia. Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2). De novo CNVs of known pathogenic significance in other genomic disorders were also observed, including deletion at the TAR (thrombocytopenia absent radius) region on 1q21.1 and duplication at the WBS (Williams-Beuren syndrome) region at 7q11.23. Multiple de novos spanned genes encoding members of the DLG (discs large) family of membrane-associated guanylate kinases (MAGUKs) that are components of the postsynaptic density (PSD). Two de novos also affected EHMT1, a histone methyl transferase known to directly regulate DLG family members. Using a systems biology approach and merging novel CNV and proteomics data sets, systematic analysis of synaptic protein complexes showed that, compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 × 10 -6). This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 × 10 -6) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 × 10 -8) postsynaptic signalling complexes. In an analysis of 18 492 subjects (7907 cases and 10 585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14). Our data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia.",
author = "G. Kirov and Pocklington, {A. J.} and P. Holmans and D. Ivanov and Masashi Ikeda and D. Ruderfer and J. Moran and K. Chambert and D. Toncheva and L. Georgieva and D. Grozeva and M. Fjodorova and R. Wollerton and E. Rees and I. Nikolov and {Van De Lagemaat}, {L. N.} and A. Bay{\'e}s and E. Fernandez and Olason, {P. I.} and Y. B{\"o}ttcher and Komiyama, {N. H.} and Collins, {M. O.} and J. Choudhary and K. Stefansson and H. Stefansson and Grant, {S. G.N.} and S. Purcell and P. Sklar and O'Donovan, {M. C.} and Owen, {M. J.}",
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Kirov, G, Pocklington, AJ, Holmans, P, Ivanov, D, Ikeda, M, Ruderfer, D, Moran, J, Chambert, K, Toncheva, D, Georgieva, L, Grozeva, D, Fjodorova, M, Wollerton, R, Rees, E, Nikolov, I, Van De Lagemaat, LN, Bayés, A, Fernandez, E, Olason, PI, Böttcher, Y, Komiyama, NH, Collins, MO, Choudhary, J, Stefansson, K, Stefansson, H, Grant, SGN, Purcell, S, Sklar, P, O'Donovan, MC & Owen, MJ 2012, 'De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia', Molecular Psychiatry, vol. 17, no. 2, pp. 142-153. https://doi.org/10.1038/mp.2011.154

De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. / Kirov, G.; Pocklington, A. J.; Holmans, P.; Ivanov, D.; Ikeda, Masashi; Ruderfer, D.; Moran, J.; Chambert, K.; Toncheva, D.; Georgieva, L.; Grozeva, D.; Fjodorova, M.; Wollerton, R.; Rees, E.; Nikolov, I.; Van De Lagemaat, L. N.; Bayés, A.; Fernandez, E.; Olason, P. I.; Böttcher, Y.; Komiyama, N. H.; Collins, M. O.; Choudhary, J.; Stefansson, K.; Stefansson, H.; Grant, S. G.N.; Purcell, S.; Sklar, P.; O'Donovan, M. C.; Owen, M. J.

In: Molecular Psychiatry, Vol. 17, No. 2, 01.02.2012, p. 142-153.

Research output: Contribution to journalArticle

TY - JOUR

T1 - De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia

AU - Kirov, G.

AU - Pocklington, A. J.

AU - Holmans, P.

AU - Ivanov, D.

AU - Ikeda, Masashi

AU - Ruderfer, D.

AU - Moran, J.

AU - Chambert, K.

AU - Toncheva, D.

AU - Georgieva, L.

AU - Grozeva, D.

AU - Fjodorova, M.

AU - Wollerton, R.

AU - Rees, E.

AU - Nikolov, I.

AU - Van De Lagemaat, L. N.

AU - Bayés, A.

AU - Fernandez, E.

AU - Olason, P. I.

AU - Böttcher, Y.

AU - Komiyama, N. H.

AU - Collins, M. O.

AU - Choudhary, J.

AU - Stefansson, K.

AU - Stefansson, H.

AU - Grant, S. G.N.

AU - Purcell, S.

AU - Sklar, P.

AU - O'Donovan, M. C.

AU - Owen, M. J.

PY - 2012/2/1

Y1 - 2012/2/1

N2 - A small number of rare, recurrent genomic copy number variants (CNVs) are known to substantially increase susceptibility to schizophrenia. As a consequence of the low fecundity in people with schizophrenia and other neurodevelopmental phenotypes to which these CNVs contribute, CNVs with large effects on risk are likely to be rapidly removed from the population by natural selection. Accordingly, such CNVs must frequently occur as recurrent de novo mutations. In a sample of 662 schizophrenia proband-parent trios, we found that rare de novo CNV mutations were significantly more frequent in cases (5.1% all cases, 5.5% family history negative) compared with 2.2% among 2623 controls, confirming the involvement of de novo CNVs in the pathogenesis of schizophrenia. Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2). De novo CNVs of known pathogenic significance in other genomic disorders were also observed, including deletion at the TAR (thrombocytopenia absent radius) region on 1q21.1 and duplication at the WBS (Williams-Beuren syndrome) region at 7q11.23. Multiple de novos spanned genes encoding members of the DLG (discs large) family of membrane-associated guanylate kinases (MAGUKs) that are components of the postsynaptic density (PSD). Two de novos also affected EHMT1, a histone methyl transferase known to directly regulate DLG family members. Using a systems biology approach and merging novel CNV and proteomics data sets, systematic analysis of synaptic protein complexes showed that, compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 × 10 -6). This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 × 10 -6) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 × 10 -8) postsynaptic signalling complexes. In an analysis of 18 492 subjects (7907 cases and 10 585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14). Our data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia.

AB - A small number of rare, recurrent genomic copy number variants (CNVs) are known to substantially increase susceptibility to schizophrenia. As a consequence of the low fecundity in people with schizophrenia and other neurodevelopmental phenotypes to which these CNVs contribute, CNVs with large effects on risk are likely to be rapidly removed from the population by natural selection. Accordingly, such CNVs must frequently occur as recurrent de novo mutations. In a sample of 662 schizophrenia proband-parent trios, we found that rare de novo CNV mutations were significantly more frequent in cases (5.1% all cases, 5.5% family history negative) compared with 2.2% among 2623 controls, confirming the involvement of de novo CNVs in the pathogenesis of schizophrenia. Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2). De novo CNVs of known pathogenic significance in other genomic disorders were also observed, including deletion at the TAR (thrombocytopenia absent radius) region on 1q21.1 and duplication at the WBS (Williams-Beuren syndrome) region at 7q11.23. Multiple de novos spanned genes encoding members of the DLG (discs large) family of membrane-associated guanylate kinases (MAGUKs) that are components of the postsynaptic density (PSD). Two de novos also affected EHMT1, a histone methyl transferase known to directly regulate DLG family members. Using a systems biology approach and merging novel CNV and proteomics data sets, systematic analysis of synaptic protein complexes showed that, compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 × 10 -6). This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 × 10 -6) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 × 10 -8) postsynaptic signalling complexes. In an analysis of 18 492 subjects (7907 cases and 10 585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14). Our data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia.

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