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De novo mutations in schizophrenia implicate synaptic networks

Published on Feb 1, 2014in Nature43.07
· DOI :10.1038/nature12929
Menachem Fromer38
Estimated H-index: 38
(MIT: Massachusetts Institute of Technology),
Andrew Pocklington24
Estimated H-index: 24
+ 29 AuthorsMichael O. Donovan122
Estimated H-index: 122
(Cardiff University)
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.
  • References (44)
  • Citations (905)
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References44
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Exome sequence analysis of more than 5,000 schizophrenia cases and controls identifies a polygenic burden primarily arising from rare, disruptive mutations distributed across many genes, among which are those encoding voltage-gated calcium ion channels and the signalling complex formed by the ARC protein of the postsynaptic density; as in autism, mutations were also found in homologues of known targets of the fragile X mental retardation protein.
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#1Jennifer C. Darnell (Rockefeller University)H-Index: 22
#2Eric KlannH-Index: 69
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SUMMARY Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specifictodevelopmentalstageandneuroanatomical structure. Weidentified denovomutationsin persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral...
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