Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder

Frank, R. A.W. et al. (2011) Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder. PLoS ONE, 6(4), e19011. (doi: 10.1371/journal.pone.0019011) (PMID:21559497) (PMCID:PMC3084736)

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Current models of schizophrenia and bipolar disorder implicate multiple genes, however their biological relationships remain elusive. To test the genetic role of glutamate receptors and their interacting scaffold proteins, the exons of ten glutamatergic ‘hub’ genes in 1304 individuals were re-sequenced in case and control samples. No significant difference in the overall number of non-synonymous single nucleotide polymorphisms (nsSNPs) was observed between cases and controls. However, cluster analysis of nsSNPs identified two exons encoding the cysteine-rich domain and first transmembrane helix of GRM1 as a risk locus with five mutations highly enriched within these domains. A new splice variant lacking the transmembrane GPCR domain of GRM1 was discovered in the human brain and the GRM1 mutation cluster could perturb the regulation of this variant. The predicted effect on individuals harbouring multiple mutations distributed in their ten hub genes was also examined. Diseased individuals possessed an increased load of deleteriousness from multiple concurrent rare and common coding variants. Together, these data suggest a disease model in which the interplay of compound genetic coding variants, distributed among glutamate receptors and their interacting proteins, contribute to the pathogenesis of schizophrenia and bipolar disorders.

Item Type:Articles
Additional Information:Research funded by Genes to Cognition Program and Wellcome Trust Functional Genomics Initiative.
Glasgow Author(s) Enlighten ID:Bradley, Dr Sophie
Authors: Frank, R. A.W., McRae, A. F., Pocklington, A. J., van de Lagemaat, L. N., Navarro, P., Croning, M. D.R., Komiyama, N. H., Bradley, S. J., Challiss, R.A. J., Armstrong, J. D., Finn, R. D., Malloy, M. P., MacLean, A. W., Harris, S. E., Starr, J. M., Bhaskar, S. S., Howard, E. K., Hunt, S. E., Coffey, A. J., Ranganath, V., Deloukas, P., Rogers, J., Muir, W. J., Deary, I. J., Blackwood, D. H., Visscher, P. M., and Grant, S. G.N.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN (Online):1932-6203
Copyright Holders:Copyright © 2011 Frank et al.
First Published:First published in PLoS ONE 6(4): e19011
Publisher Policy:Reproduced under a Creative Commons license

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