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Abstract

Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose messenger RNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case–control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders.

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  • 12 February 2014

    The link in reference 15 was incorrect and has been fixed.

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Data deposits

Data included in this manuscript have been deposited at dbGaP under accession number phs000687.v1.p1 and is available for download at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000687.v1.p1.

References

  1. 1.

    , & Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nature Rev. Genet. 13, 537–551 (2012)

  2. 2.

    , & A systematic review and meta-analysis of the fertility of patients with schizophrenia and their unaffected relatives. Acta Psychiatr. Scand. 123, 98–106 (2011)

  3. 3.

    , & Schizophrenia: a common disease caused by multiple rare alleles. Br. J. Psychiatry 190, 194–199 (2007)

  4. 4.

    & Genetics: Fish heads and human disease. Nature 485, 318–319 (2012)

  5. 5.

    , , , & De novo rates and selection of schizophrenia-associated copy number variants. Biol. Psychiatry 70, 1109–1114 (2011)

  6. 6.

    et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012)

  7. 7.

    et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012)

  8. 8.

    et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012)

  9. 9.

    et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012)

  10. 10.

    et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380, 1674–1682 (2012)

  11. 11.

    et al. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367, 1921–1929 (2012)

  12. 12.

    et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nature Genet. 43, 860–863 (2011)

  13. 13.

    et al. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nature Genet. 44, 1365–1369 (2012)

  14. 14.

    et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154, 518–529 (2013)

  15. 15.

    et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature (22 January 2014)

  16. 16.

    et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature 488, 471–475 (2012)

  17. 17.

    , , & V & Seidman, L. J. Neurocognition in first-episode schizophrenia: a meta-analytic review. Neuropsychology 23, 315–336 (2009)

  18. 18.

    et al. Strong synaptic transmission impact by copy number variations in schizophrenia. Proc. Natl Acad. Sci. USA 107, 10584–10589 (2010)

  19. 19.

    et al. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 72, 951–963 (2011)

  20. 20.

    et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol. Psychiatry 17, 142–153 (2012)

  21. 21.

    et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011)

  22. 22.

    & NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci. 16, 521–527 (1993)

  23. 23.

    et al. The Arc of synaptic memory. Exp. Brain Res. 200, 125–140 (2010)

  24. 24.

    & Arc in synaptic plasticity: from gene to behavior. Trends Neurosci. 34, 591–598 (2011)

  25. 25.

    & New views of Arc, a master regulator of synaptic plasticity. Nature Neurosci. 14, 279–284 (2011)

  26. 26.

    et al. Arc/Arg3.1 Is a postsynaptic mediator of activity-dependent synapse elimination in the developing cerebellum. Neuron 78, 1024–1035 (2013)

  27. 27.

    Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J. Psychiatr. Res. 17, 319–334 (1982)

  28. 28.

    & The translation of translational control by FMRP: therapeutic targets for FXS. Nature Neurosci. 16, 1530–1536 (2013)

  29. 29.

    et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nature Genet. 25 25–29 (2000)

  30. 30.

    et al. Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70, 898–907 (2011)

  31. 31.

    et al. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 485, 363–367 (2012)

  32. 32.

    et al. Common variants at VRK2 and TCF4 conferring risk of schizophrenia. Hum. Mol. Genet. 20, 4076–4081 (2011)

  33. 33.

    et al. SynSysNet: integration of experimental data on synaptic protein-protein interactions with drug-target relations. Nucleic Acids Res. 41, D834–D840 (2013)

  34. 34.

    , , , & Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking. Cell 154, 75–88 (2013)

  35. 35.

    et al. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet 376, 1401–1408 (2010)

  36. 36.

    et al. Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N. Engl. J. Med. 367, 1321–1331 (2012)

  37. 37.

    , , & Neurodevelopmental hypothesis of schizophrenia. Br. J. Psychiatry 198, 173–175 (2011)

  38. 38.

    et al. Human POGZ modulates dissociation of HP1α from mitotic chromosome arms through Aurora B activation. Nature Cell Biol. 12, 719–727 (2010)

  39. 39.

    et al. The autism sequencing consortium: large-scale, high-throughput sequencing in autism spectrum disorders. Neuron 76, 1052–1056 (2012)

  40. 40.

    & The Kraepelinian dichotomy – going, going...but still not gone. Br. J. Psychiatry 196, 92–95 (2010)

  41. 41.

    Transforming diagnosis. NIMH Director’s Blog (29 April 2013)

  42. 42.

    , & Organization of brain complexity–synapse proteome form and function. Brief. Funct. Genomics Proteomics 5, 66–73 (2006)

  43. 43.

    et al. TNiK is required for postsynaptic and nuclear signaling pathways and cognitive function. J. Neurosci. 32, 13987–13999 (2012)

  44. 44.

    et al. A family-based study of common polygenic variation and risk of schizophrenia. Mol. Psychiatry 16, 887–888 (2011)

Download references

Acknowledgements

Work in Cardiff was supported by Medical Research Council (MRC) Centre (G0800509) and Program Grants (G0801418), the European Community’s Seventh Framework Programme (HEALTH-F2-2010-241909 (Project EU-GEI)), and NIMH (2 P50 MH066392-05A1). Work at the Icahn School of Medicine at Mount Sinai was supported by the Friedman Brain Institute, the Institute for Genomics and Multiscale Biology (including computational resources and staff expertise provided by the Department of Scientific Computing), and National Institutes of Health grants R01HG005827 (S.M.P.), R01MH099126 (S.M.P.), and R01MH071681 (P.S.). Work at the Broad Institute was funded by Fidelity Foundations, the Sylvan Herman Foundation, philanthropic gifts from K. and E. Dauten, and the Stanley Medical Research Institute. Work at the Wellcome Trust Sanger Institute was supported by The Wellcome Trust (grant numbers WT089062 and WT098051) and also by the European Commission FP7 project gEUVADIS no. 261123 (P.P.). We would like to thank M. Daly, B. Neale and K. Samocha for discussions and providing unpublished autism data. We would also like to acknowledge M. DePristo, S. Gabriel, T. J. Fennel, K. Shakir, C. Tolonen and H. Shah for their help in generating and processing the various data sets.

Author information

Affiliations

  1. Division of Psychiatric Genomics in the Department of Psychiatry, and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Menachem Fromer
    • , Douglas M. Ruderfer
    • , Jessica S. Johnson
    • , Panos Roussos
    • , Milind Mahajan
    • , Pamela Sklar
    •  & Shaun M. Purcell
  2. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    • Menachem Fromer
    • , Douglas D. Barker
    • , Samuel A. Rose
    • , Kimberly Chambert
    • , Edward M. Scolnick
    • , Jennifer L. Moran
    • , Steven A. McCarroll
    •  & Shaun M. Purcell
  3. Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK

    • Andrew J. Pocklington
    • , David H. Kavanagh
    • , Hywel J. Williams
    • , Sarah Dwyer
    • , Lyudmila Georgieva
    • , Elliott Rees
    • , Douglas M. Ruderfer
    • , Noa Carrera
    • , Isla Humphreys
    • , Eilis Hannon
    • , George Kirov
    • , Peter Holmans
    • , Michael J. Owen
    •  & Michael C. O’Donovan
  4. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK

    • Padhraig Gormley
    • , Priit Palta
    •  & Aarno Palotie
  5. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    • Padhraig Gormley
    • , Eric Banks
    • , Aarno Palotie
    •  & Steven A. McCarroll
  6. Department of Bioinformatics, Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia

    • Priit Palta
  7. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00290 Helsinki, Finland

    • Priit Palta
    •  & Aarno Palotie
  8. Department of Psychiatry, Medical University, Sofia 1431, Bulgaria

    • Vihra Milanova
  9. Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4SB, UK

    • Seth G. Grant
  10. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Steven A. McCarroll
  11. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Pamela Sklar
  12. Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Shaun M. Purcell

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Contributions

The project was led in Cardiff by M.C.O.D. and M.J.O., in Mount Sinai by S.M.P. and P.S., at the Broad by S.A.M. and J.L.M., and at the Sanger by A.P.; H.J.W., J.L.M., K.C., J.S.J., D.D.B., M.M. and S.A.R. were responsible for sample processing and data management. M.F., H.J.W., P.G., D.M.R., D.H.K., G.K., E.R. and S.D. processed NGS data, annotated and validated mutations. L.G., N.C., I.H., S.D., H.J.W. and S.A.R. undertook validation of mutations and additional lab work. A.J.P., M.F., D.H.K., S.M.P. and P.H. co-ordinated/undertook the main bioinformatics/statistical analyses. E.R., D.M.R., E.B., P.P., E.H. and P.R. performed additional analyses. S.G.G. contributed additional insights into synaptic biology. Sample recruitment was led by G.K. and V.M.; The main findings were interpreted by M.C.O.D., M.F., M.J.O., P.H., G.K., E.M.S., S.A.M., D.H.K., A.J.P., A.P., S.M.P. and P.S. who drafted the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael J. Owen.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Text and additional references.

Excel files

  1. 1.

    Supplementary Table 1

    This file contains a list of validated coding de novo mutations discovered in subjects with schizophrenia. For each de novo mutation (single-nucleotide or insertion/deletion variant) discovered in a proband with schizophrenia in this study, listed are basic details, including genomic coordinates (hg19), reference and de novo alleles, functional impact in genes overlapped (see Supplementary Text), number of total alternate alleles called at that locus in this sample (N=623 trios, including parental genotypes), sequencing metrics for the genotypes (in the proband, father, and mother), the phased parent-of-origin when known, and family history (first-degree relatives).

  2. 2.

    Supplementary Table 2

    The file contains a compiled list of published de novo mutations in unaffected controls and individuals with neuropsychiatric illness. Sheet 1 shows de novo mutations analyzed alongside the schizophrenia mutations in this study, counts of individuals and RefSeq-coding mutations from published study sources, neuropsychiatric phenotype, and first author of study source are given. ASD = autism spectrum disorders, CONTROL = individual from unaffected family, ID = intellectual disability, SZ = schizophrenia, SIB = unaffected sibling of proband (from families with sequenced “quads” = father, mother, child with ASD or SZ, unaffected sibling). Sheet 2 shows that for the studies and sample sizes listed in the sheet 1, all published de novo mutations were collated and uniformly annotated. Note that only those annotated as RefSeq-coding by Plink/Seq (see Supplementary Text) are listed here. Columns are as described in Table S1.

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DOI

https://doi.org/10.1038/nature12929

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