title: Further evidence for a functional role of the glutamate receptor gene GRM3 in schizophrenia.
abstract: In recent years, evidence has been accumulating indicating a major role of glutamate in the pathogenesis and pathophysiology of schizophrenia. Of particular importance in this regard are the metabotropic glutamate receptors (GRM). Thus, a recently published trial of the amino acid analogue LY2140023, which exerts its effects through the activation of the glutamate receptors GRM3/GRM2, showed an improvement of positive and negative symptoms comparable to treatment with olanzapine. A functional variant of GRM3 has been described which modulates synaptic glutamate levels. We assessed whether this functional variant rs6465084 is related to schizophrenia in a large sample of patients and controls. We found an increased frequency of the A allele (p=0.027) and the AA genotype (p=0.024) in schizophrenia patients. Moreover, in an assessment of schizophrenia endophenotypes, patients of the AA genotype performed poorly in the digit symbol test, a measure of attention (p=0.008). Our results provide further evidence for the potential importance of the glutamate receptor GRM3 in schizophrenia, and indicate that the novel antipsychotic LY2140023 may actually be targeting a pathogenic pathway of schizophrenia.
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Bonn, Sigmund-Freud-Strasse 25, Germany. rainald.moessner@ukb.uni-bonn.de
authors.forename: Rainald
authors.initials: R
authors.lastname: Mössner
authors.forename: Anna
authors.initials: A
authors.lastname: Schuhmacher
authors.forename: Svenja
authors.initials: S
authors.lastname: Schulze-Rauschenbach
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Kühn
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Astrid
authors.initials: A
authors.lastname: Zobel
authors.forename: Petra
authors.initials: P
authors.lastname: Franke
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wölwer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Gaebel
authors.forename: Heinz
authors.initials: H
authors.lastname: Häfner
authors.forename: Michael
authors.initials: M
authors.lastname: Wagner
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
mesh_terms: D000328:Adult; D000596:Amino Acids / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001569:Benzodiazepines / Q000627:therapeutic use; D016009:Chi-Square Distribution; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D000077152:Olanzapine; D010597:Pharmacogenetics; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; C534551:LY 2140023; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; D001569:Benzodiazepines; D000077152:Olanzapine