Scientific Understanding of Consciousness
Schizophrenia Mutations in Synaptic Networks
Nature 506, 179–184 (13 February 2014)
De novo mutations in schizophrenia implicate synaptic networks
Menachem Fromer, et.al.
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
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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
Department of Psychiatry, Medical University, Sofia 1431, Bulgaria
Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4SB, UK
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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.
Schizophrenia is a disorder whose pathophysiology is largely unknown. It has a lifetime risk of about 1%, is frequently chronic and socially disabling, and is associated with an average reduction in lifespan of about 25 years. High heritability points to a major role for transmitted genetic variants. However, it is also associated with a marked reduction in fecundity, leading to the hypothesis that alleles with large effects on risk might often occur de novo (mutations present in affected individual but not in either parent) to balance their elimination from the population by selection.
Of the known risk alleles for schizophrenia, the only ones definitively shown to confer considerable increments in risk are rare chromosomal copy number variants (CNVs), which involve deletion or duplication of thousands of bases of DNA. As predicted by the association of schizophrenia with decreased fecundity, these CNVs often occur de novo in the small proportion of cases in which they are found. Exome sequencing technology now allows systematic scans of genes for de novo mutations at single-base rather than kilobase resolution. This approach has already implicated de novo loss-of-function mutations in disorders in which, as in schizophrenia, de novo CNVs have a role, including autism spectrum disorder (ASD) and intellectual disability. In schizophrenia, the results from exome sequencing do not yet support definitive conclusions, probably owing to limited sample sizes.
We report the largest exome sequencing study of de novo mutations in schizophrenia to date, using genomic (blood) DNA from 623 schizophrenia trios. The primary aims were fourfold. The first two aims were to establish a general case for the relevance of de novo mutations in schizophrenia by determining whether de novo mutations affecting protein sequences occur in schizophrenia at higher than expected rates or are enriched among sets of genes implicated in the disorder through other approaches. The remaining two aims, the main motivation for the study, were to determine whether de novo mutations implicate specific pathogenic biological processes in schizophrenia and to investigate the relationship between schizophrenia and other neurodevelopmental disorders. To test for reproducibility, and ensure robustness of the findings to study design, we shared our findings with an independent case–control exome sequencing study.
In the largest exome-sequencing-based study of de novo mutations in schizophrenia, we demonstrate a convergence of de novo mutations on multiply defined sets of functionally related proteins, pointing to the regulation of plasticity at glutamatergic synapses as a pathogenic mechanism in schizophrenia. How disruption of these synaptic mechanisms affects brain function to produce psychopathology cannot be answered by genetic studies alone, but our identification of de novo mutations in these gene sets provides the basis to address this. Our findings of overlaps between the pathogenic mechanisms underlying schizophrenia and those in autism and intellectual disability lend support to recent, controversial suggestions that our understanding of these disorders might be advanced better by research that integrates findings across multiple disorders and places more emphasis on domains of psychopathology (for example, cognition) and their neurobiological substrates rather than current diagnostic categories.
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