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Biol Psychiatry. 2015 Jan 1;77(1):52-8. doi: 10.1016/j.biopsych.2014.07.011. Epub 2014 Jul 18.

Genetic risk for schizophrenia: convergence on synaptic pathways involved in plasticity.

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  • 1Medical Research Council Centre for Neuropsychiatric Genetics and Genomics; Neuroscience and Mental Health Research Institute. Electronic address:
  • 2Neuroscience and Mental Health Research Institute.
  • 3Neuroscience and Mental Health Research Institute; Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom.
  • 4Medical Research Council Centre for Neuropsychiatric Genetics and Genomics.
  • 5Medical Research Council Centre for Neuropsychiatric Genetics and Genomics; Neuroscience and Mental Health Research Institute.


Recent large-scale genomic studies have revealed two broad classes of risk alleles for schizophrenia: a polygenic component of risk mediated through multiple common risk variants and rarer more highly penetrant submicroscopic chromosomal deletions and duplications, known as copy number variants. The focus of this review is on the emerging findings from the latter and subsequent exome sequencing data of smaller, deleterious single nucleotide variants and indels. In these studies, schizophrenia patients were found to have enriched de novo mutations in genes belonging to the postsynaptic density at glutamatergic synapses, particularly components of the N-methyl-D-aspartate receptor signaling complex, including the PSD-95 complex, activity-regulated cytoskeleton-associated protein interactors, the fragile X mental retardation protein complex, voltage-gated calcium channels, and genes implicated in actin cytoskeletal dynamics. The convergence of these implicated genes onto a coherent biological pathway at the synapse, with a specific role in plasticity, provides a significant advance in understanding pathogenesis and points to new targets for biological investigation. We consider the implications of these studies in the context of existing genetic data and the potential need to reassess diagnostic boundaries of neuropsychiatric disorders before discussing ways forward for more directed mechanistic studies to develop stratified, novel therapeutic approaches in the future.

Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.


ARC, Genetics; Actin; NMDA; Schizophrenia; Synapse

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