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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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Change history

  • 12 February 2014

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


Data deposits

Data included in this manuscript have been deposited at dbGaP under accession number phs000687.v1.p1 and is available for download at


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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


  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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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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