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De novo mutations in schizophrenia implicate synaptic networks

Author

Listed:
  • Menachem Fromer

    (and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Andrew J. Pocklington

    (Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK)

  • David H. Kavanagh

    (Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK)

  • Hywel J. Williams

    (Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK)

  • Sarah Dwyer

    (Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK)

  • Padhraig Gormley

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Lyudmila Georgieva

    (Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK)

  • Elliott Rees

    (Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK)

  • Priit Palta

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
    Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00290 Helsinki, Finland)

  • Douglas M. Ruderfer

    (and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
    Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK)

  • Noa Carrera

    (Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK)

  • Isla Humphreys

    (Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK)

  • Jessica S. Johnson

    (and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai)

  • Panos Roussos

    (and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai)

  • Douglas D. Barker

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Eric Banks

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Vihra Milanova

    (Medical University, Sofia 1431, Bulgaria)

  • Seth G. Grant

    (Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4SB, UK)

  • Eilis Hannon

    (Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK)

  • Samuel A. Rose

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Kimberly Chambert

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Milind Mahajan

    (and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai)

  • Edward M. Scolnick

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Jennifer L. Moran

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • George Kirov

    (Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK)

  • Aarno Palotie

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00290 Helsinki, Finland)

  • Steven A. McCarroll

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Peter Holmans

    (Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK)

  • Pamela Sklar

    (and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
    Friedman Brain Institute, Icahn School of Medicine at Mount Sinai)

  • Michael J. Owen

    (Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK)

  • Shaun M. Purcell

    (and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital)

  • Michael C. O’Donovan

    (Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK)

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.

Suggested Citation

  • Menachem Fromer & Andrew J. Pocklington & David H. Kavanagh & Hywel J. Williams & Sarah Dwyer & Padhraig Gormley & Lyudmila Georgieva & Elliott Rees & Priit Palta & Douglas M. Ruderfer & Noa Carrera &, 2014. "De novo mutations in schizophrenia implicate synaptic networks," Nature, Nature, vol. 506(7487), pages 179-184, February.
    • Handle: RePEc:nat:nature:v:506:y:2014:i:7487:d:10.1038_nature12929
    DOI: 10.1038/nature12929
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    Cited by:

    1. Yuni Kay & Linda Tsan & Elizabeth A. Davis & Chen Tian & Léa Décarie-Spain & Anastasiia Sadybekov & Anna N. Pushkin & Vsevolod Katritch & Scott E. Kanoski & Bruce E. Herring, 2022. "Schizophrenia-associated SAP97 mutations increase glutamatergic synapse strength in the dentate gyrus and impair contextual episodic memory in rats," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Marco Colizzi & Riccardo Bortoletto & Rosalia Costa & Sagnik Bhattacharyya & Matteo Balestrieri, 2022. "The Autism–Psychosis Continuum Conundrum: Exploring the Role of the Endocannabinoid System," IJERPH, MDPI, vol. 19(9), pages 1-22, May.
    3. Karen Perez Arce & Adema Ribic & Dhrubajyoti Chowdhury & Katherine Watters & Garth J. Thompson & Basavaraju G. Sanganahalli & Elizabeth T. C. Lippard & Astrid Rohlmann & Stephen M. Strittmatter & Mark, 2023. "Concerted roles of LRRTM1 and SynCAM 1 in organizing prefrontal cortex synapses and cognitive functions," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Ralda Nehme & Olli Pietiläinen & Mykyta Artomov & Matthew Tegtmeyer & Vera Valakh & Leevi Lehtonen & Christina Bell & Tarjinder Singh & Aditi Trehan & John Sherwood & Danielle Manning & Emily Peirent , 2022. "The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    5. Christina Kyrousi & Adam C. O’Neill & Agnieska Brazovskaja & Zhisong He & Pavel Kielkowski & Laure Coquand & Rossella Giaimo & Pierpaolo D’ Andrea & Alexander Belka & Andrea Forero Echeverry & Davide , 2021. "Extracellular LGALS3BP regulates neural progenitor position and relates to human cortical complexity," Nature Communications, Nature, vol. 12(1), pages 1-22, December.

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