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De novo mutations in schizophrenia implicate synaptic networks

机译：精神分裂症的从头突变意味着突触网络

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摘要

本期Nature发表了对精神分裂症患者及其亲属所做的两项重要外显子组（基因组的蛋白编码部分）测序研究。这两项研究一起为了解在精神分裂症中破坏谷氨酸能突触的特定致机制提供了可靠线索。影响支架蛋白ARC("活性调控的与细胞骨架相关的蛋白")功能的突变在其中的参与尤为明显，"脆弱X智力迟钝蛋白"(FMRP)的目标中所发生的突变也是这样。FMRP的缺陷以前曾被发现与"泛自闭症"有关。%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 iV-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.
机译：本期Nature发表了对精神分裂症患者及其亲属所做的两项重要外显子组（基因组的蛋白编码部分）测序研究。这两项研究一起为了解在精神分裂症中破坏谷氨酸能突触的特定致机制提供了可靠线索。影响支架蛋白ARC("活性调控的与细胞骨架相关的蛋白")功能的突变在其中的参与尤为明显，"脆弱X智力迟钝蛋白"(FMRP)的目标中所发生的突变也是这样。FMRP的缺陷以前曾被发现与"泛自闭症"有关。%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 iV-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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  • 来源
    《Nature》 |2014年第7487期|179-184121|共7页
  • 作者

    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; Isla Humphreys; Jessica S. Johnson; Panos Roussos; Douglas D. Barker; Eric Banks; Vihra Milanova; Seth G. Grant; Eilis Hannon; Samuel A. Rose; Kimberly Chambert; Milind Mahajan; Edward M. Scolnick; Jennifer L. Moran; George Kirov; Aarno Palotie; Steven A. McCarroll; Peter Holmans; Pamela Sklar; Michael J. Owen; Shaun M Purcell; Michael C. ODonovan;

  • 作者单位

    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,Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;

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

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

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

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

    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 ISA, UK,Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;

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

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

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

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

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

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

    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;

    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;

    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;

    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;

    Department of Psychiatry, Medical University, Sofia 1431, Bulgaria;

    Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH164SB, UK;

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

    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;

    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;

    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;

    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;

    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;

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

    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 ISA, UK,Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA,Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00290 Helsinki, Finland;

    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA,Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA,Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;

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

    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,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;

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

    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,Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA,Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;

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

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