Clustered Coding Variants in the Glutamate Receptor Complexes of Individuals with Schizophrenia and Bipolar Disorder

Rene A. W. Frank, Allan F. McRae, Andrew J. Pocklington, Louie Van De Lagemaat, Pau Navarro, Mike D. R. Croning, Noboru H. Komiyama, Sophie J. Bradley, R. A. John Challiss, J. Douglas Armstrong, Robert D. Finn, Mary P. Malloy, Alan W. MacLean, Sarah E. Harris, John Starr, Sanjeev S. Bhaskar, Eleanor K. Howard, Sarah E. Hunt, Alison J. Coffey, Venkatesh RanganathPano Deloukas, Jane Rogers, Walter J. Muir, Ian J. Deary, Douglas H. Blackwood, Peter M. Visscher, Seth G. N. Grant

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Article numbere19011
Pages (from-to)-
Number of pages9
JournalPLoS ONE
Volume6
Issue number4
DOIs
Publication statusPublished - 29 Apr 2011

Keywords / Materials (for Non-textual outputs)

  • Bipolar Disorder
  • Case-Control Studies
  • Cluster Analysis
  • Exons
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genotype
  • Humans
  • Mutation
  • Polymorphism, Single Nucleotide
  • Protein Structure, Tertiary
  • Receptors, Glutamate
  • Schizophrenia
  • Sequence Analysis, DNA

Fingerprint

Dive into the research topics of 'Clustered Coding Variants in the Glutamate Receptor Complexes of Individuals with Schizophrenia and Bipolar Disorder'. Together they form a unique fingerprint.

Cite this