title: Genetic association, mutation screening, and functional analysis of a Kozak sequence variant in the metabotropic glutamate receptor 3 gene in bipolar disorder.
abstract: OBJECTIVE
  Genetic markers at the gene encoding the metabotropic glutamate receptor 3 (GRM3) showed allelic association with bipolar disorder.
  
  
  OBJECTIVE
  To screen the GRM3 gene and adjacent control regions of genomic DNA in volunteers with bipolar affective disorder for mutations increasing susceptibility to bipolar disorder.
  
  
  METHODS
  Sequencing and high-resolution melting curve analysis of DNA followed by genotyping was carried out in 1099 patients with bipolar affective disorder and 1152 healthy comparator individuals.
  
  
  METHODS
  Participants with bipolar disorder were recruited from National Health Service psychiatric services and from patient organizations.
  
  
  METHODS
  Individuals were included if they had Research Diagnostic Criteria diagnoses of bipolar I and bipolar II disorder and were of British or Irish ancestry.
  
  
  METHODS
  Identification of base pair changes in the GRM3 gene that affected expression or function of the GRM3 receptor that also showed an allelic association with bipolar disorder.
  
  
  RESULTS
  A base pair variant (rs148754219) was found in the Kozak sequence of exon 1 of the GRM3 gene, 2 bases before the translation start codon of one of the receptor isoforms, in 23 of 2251 people who were screened and genotyped. Nineteen of the 1099 bipolar cases (1.7%) were mutation carriers compared with 4 of 1152 healthy comparators (0.3%). The variant was associated with bipolar disorder (P = .005; odds ratio, 4.20). Bioinformatic, electrophoretic mobility shift assay, and gene expression analysis found that the variant created a new transcription factor protein binding site and had a strong effect on gene transcription and translation.
  
  
  CONCLUSIONS
  Confirmation of these findings is needed before the Kozak sequence variant can be accepted as a potential marker for personalized treatment of affective disorders with drugs targeting the metabotropic glutamate receptor 3.
authors.affiliation: Molecular Psychiatry Laboratory, Mental Health Sciences Unit, University College London, UK.
authors.forename: Radhika
authors.initials: R
authors.lastname: Kandaswamy
authors.forename: Andrew
authors.initials: A
authors.lastname: McQuillin
authors.forename: Sally I
authors.initials: SI
authors.lastname: Sharp
authors.forename: Alessia
authors.initials: A
authors.lastname: Fiorentino
authors.forename: Adebayo
authors.initials: A
authors.lastname: Anjorin
authors.forename: Robert A
authors.initials: RA
authors.lastname: Blizard
authors.forename: David
authors.initials: D
authors.lastname: Curtis
authors.forename: Hugh M D
authors.initials: HM
authors.lastname: Gurling
mesh_terms: D000483:Alleles; D020137:Base Pair Mismatch / Q000235:genetics; D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D024202:Electrophoretic Mobility Shift Assay; D056726:Genetic Association Studies; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics*
chemical_list: D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3