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Genetic risk for schizophrenia: convergence on synaptic pathways Involved in plasticity

Hall, Jeremy ORCID:, Trent, Simon ORCID:, Thomas, Kerrie Lorraine ORCID:, O'Donovan, Michael Conlon ORCID: and Owen, Michael John ORCID: 2015. Genetic risk for schizophrenia: convergence on synaptic pathways Involved in plasticity. Biological Psychiatry 77 (1) , pp. 52-68. 10.1016/j.biopsych.2014.07.011

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: Q Science > QR Microbiology
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords: Actin; ARC, genetics; NMDA; schizophrenia; synapse
Publisher: Elsevier
ISSN: 0006-3223
Date of Acceptance: 1 July 2014
Last Modified: 27 Oct 2022 09:08

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