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

Frank, Rene A. W., McRae, Allan F., Pocklington, Andrew J., van de Lagemaat, Louie N., Navarro, Pau, Croning, Mike D. R., Komiyama, Noboru H., Bradley, Sophie J., Challiss, R. A. John, Armstrong, J. Douglas, Finn, Robert D., Malloy, Mary P., MacLean, Alan W., Harris, Sarah E., Starr, John M., Bhaskar, Sanjeev S., Howard, Eleanor K., Hunt, Sarah E., Coffey, Alison J., Ranganath, Venkatesh, Deloukas, Panos, Rogers, Jane, Muir, Walter J., Deary, Ian J., Blackwood, Douglas H., Visscher, Peter M. and Grant, Seth G. N. (2011) Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder. PLoS One, 6 4: e19011.1-e19011.9. doi:10.1371/journal.pone.0019011

Author Frank, Rene A. W.
McRae, Allan F.
Pocklington, Andrew J.
van de Lagemaat, Louie N.
Navarro, Pau
Croning, Mike D. R.
Komiyama, Noboru H.
Bradley, Sophie J.
Challiss, R. A. John
Armstrong, J. Douglas
Finn, Robert D.
Malloy, Mary P.
MacLean, Alan W.
Harris, Sarah E.
Starr, John M.
Bhaskar, Sanjeev S.
Howard, Eleanor K.
Hunt, Sarah E.
Coffey, Alison J.
Ranganath, Venkatesh
Deloukas, Panos
Rogers, Jane
Muir, Walter J.
Deary, Ian J.
Blackwood, Douglas H.
Visscher, Peter M.
Grant, Seth G. N.
Title Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2011
Year available 2011
Sub-type Article (original research)
DOI 10.1371/journal.pone.0019011
Open Access Status DOI
Volume 6
Issue 4
Start page e19011.1
End page e19011.9
Total pages 9
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Collection year 2012
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
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Created: Tue, 02 Apr 2013, 13:33:38 EST by Allan Mcrae on behalf of UQ Diamantina Institute