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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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.
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 We would like to thank M. Daly, B. Neale and K. Samocha for discussions and providing unpublished autism data.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.
Extended data figures
Extended data tables
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).
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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The role of polygenic risk score gene-set analysis in the context of the omnigenic model of schizophrenia