Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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

Frank, René A.W., McRae, Allan F., Pocklington, Andrew ORCID:, 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. 10.1371/journal.pone.0019011

[thumbnail of Frank 2011.pdf]
PDF - Published Version
Available under License Creative Commons Attribution.

Download (590kB) | Preview


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: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Publisher: Public Library of Science
ISSN: 1932-6203
Date of First Compliant Deposit: 30 March 2016
Last Modified: 08 Nov 2023 20:44

Citation Data

Cited 54 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item


Downloads per month over past year

View more statistics