We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Clustered Coding Variants in the Glutamate Receptor Complexes of Individuals with Schizophrenia and Bipolar Disorder.
- Authors
Frank, René 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
- 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.
- Subjects
MEDICAL research; SCHIZOPHRENIA; BIPOLAR disorder; GENES; GENETIC mutation; GLUTAMIC acid; GENETIC polymorphisms; NUCLEOTIDE sequence; PROTEINS
- Publication
PLoS ONE, 2011, Vol 6, Issue 4, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0019011