title: Association study of the GSK-3B gene with tardive dyskinesia in European Caucasians.
abstract: There is solid evidence of a genetic predisposition to tardive dyskinesia (TD) although the pathophysiological mechanisms of TD are still unclear. Nevertheless, the dopamine overactivity hypothesis of the TD etiology receives support from both pharmacological and physiological evidence. Dopaminergic signaling modulates the glycogen synthase kinase 3B (GSK-3B), a kinase that may play a critical role in the pathogenesis of neurodegenerative diseases. GSK-3B is an essential element of the apoptotic signaling cascade induced by oxidative stress, which may be involved in TD pathogenesis. We investigated whether GSK-3B polymorphisms (rs11919783, rs6805251, rs7624540, rs6438552, rs4072520, rs9878473, rs6779828 and rs3755557) selected using tagging method were associated with TD manifestation and abnormal involuntary movement severity. We evaluated 215 schizophrenia subjects from whom 169 were European Caucasians. All eight evaluated variants had their minor allele carriers consistently showing lower risk to TD and lower Abnormal Involuntary Movement Scale. The rs6805251, rs6438552 and rs9878473 variants showed a trend for association with TD in European Caucasian subjects (permuted p=0.07). Furthermore, all tested markers showed p< or =0.0007 after we incorporated age as covariate in the analysis of the abnormal involuntary movement severity. Our results suggest that GSK-3B polymorphism may play a role in the genetic vulnerability to TD manifestation in schizophrenia subjects with European Caucasian background further implicating polymorphisms in the dopamine D2-like receptor signaling in this context. These findings should be read with caution particularly before independent replication.
authors.affiliation: Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. renanrps@yahoo.com.br
authors.forename: Renan P
authors.initials: RP
authors.lastname: Souza
authors.forename: Gary
authors.initials: G
authors.lastname: Remington
authors.forename: Nabilah I
authors.initials: NI
authors.lastname: Chowdhury
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Lau
authors.forename: Aristotle N
authors.initials: AN
authors.lastname: Voineskos
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lieberman
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
mesh_terms: D000328:Adult; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009069:Movement Disorders / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000235:genetics* / Q000503:physiopathology; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: D017448:Receptors, Dopamine D2; D038362:Glycogen Synthase Kinase 3; D004298:Dopamine