title: Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder.
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.
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, United Kingdom.
authors.forename: René A W
authors.initials: RA
authors.lastname: Frank
authors.forename: Allan F
authors.initials: AF
authors.lastname: McRae
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pocklington
authors.forename: Louie N
authors.initials: LN
authors.lastname: van de Lagemaat
authors.forename: Pau
authors.initials: P
authors.lastname: Navarro
authors.forename: Mike D R
authors.initials: MD
authors.lastname: Croning
authors.forename: Noboru H
authors.initials: NH
authors.lastname: Komiyama
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Bradley
authors.forename: R A John
authors.initials: RA
authors.lastname: Challiss
authors.forename: J Douglas
authors.initials: JD
authors.lastname: Armstrong
authors.forename: Robert D
authors.initials: RD
authors.lastname: Finn
authors.forename: Mary P
authors.initials: MP
authors.lastname: Malloy
authors.forename: Alan W
authors.initials: AW
authors.lastname: MacLean
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Harris
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.forename: Sanjeev S
authors.initials: SS
authors.lastname: Bhaskar
authors.forename: Eleanor K
authors.initials: EK
authors.lastname: Howard
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Hunt
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Coffey
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Ranganath
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Jane
authors.initials: J
authors.lastname: Rogers
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Muir
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Blackwood
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
authors.forename: Seth G N
authors.initials: SG
authors.lastname: Grant
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D016000:Cluster Analysis; D005091:Exons; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D017470:Receptors, Glutamate / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D017470:Receptors, Glutamate