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Title: Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder
Authors: Frank, R. A. W.
van de Lagemaat L. N.
Croning, M. D. R.
Komiyama, N. H.
Finn, R. D.
Bhaskar, S. S.
Howard, E. K.
Hunt, S. E.
Coffey, A. J.
Ranganath, V.
Deloukas, P.
Rogers, J.
Grant, S. G. N.
McRae, A. F.
Visscher, P. M.
Pocklington, A. J.
Armstrong, J. D.
Navarro, P.
Malloy, M. P.
MacLean, A. W.
Muir, W. J.
Blackwood, D. H.
Harris, S. E.
Starr, J. M.
Deary, I. J.
Bradley, S. J.
Challiss, R. A. J.
First Published: 29-Apr-2011
Publisher: Public Library of Science
Citation: PLoS ONE, 2011, 6(4), e19011
Abstract: 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.
DOI Link: 10.1371/journal.pone.0019011
eISSN: 1932-6203
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: © 2011 Frank et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Cell Physiology and Pharmacology

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