title: Glial cell line-derived neurotrophic factor receptor alpha 2 (GFRA2) gene is associated with tardive dyskinesia.
abstract: BACKGROUND
  Tardive dyskinesia (TD) has a pharmacogenetic component in which the interaction of antipsychotic exposure with individual genetic variation mediates risk. The glial cell line-derived neurotrophic factor (GDNF) signalling pathway has been associated with neuroprotective effects in central dopaminergic neurons and spinal motor neurons. Clinical trials have also investigated whether GDNF may ameliorate Parkinson's disease symptoms.
  
  
  METHODS
  We tested whether variants in the GDNF receptor alpha 2 (GFRA2) gene could play a role in TD susceptibility evaluating 16 variants in 172 Caucasian schizophrenia subjects.
  
  
  RESULTS
  We observed one significant allelic association (rs4739285, permuted p = 0.042) and two genotypic associations: rs4739285 under additive inheritance model and rs4739217 under dominant inheritance model (permuted p = 0.044). Moreover, carriers of the major alleles for both rs6587002 and rs4739217 presented significantly higher risk for TD (OR = 2.04, permuted p = 0.014), while subjects with the minor allele for rs4739217 and the major allele for rs6988470 were less likely to have TD (OR = 0.21, permuted p = 0.0007).
  
  
  CONCLUSIONS
  Haplotype results indicate that the minor allele of the rs4739217 is a risk factor for TD (permuted allelic p = 0.074). Age was also a risk factor for TD in our sample (p = 0.0001). Taken together, our findings suggest that GFRA2 genetic variants and age may play a role in TD susceptibility, but further work is required to confirm these findings.
authors.affiliation: Neurogenetics Section, Neuroscience Department, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Renan P
authors.initials: RP
authors.lastname: Souza
authors.forename: Vincenzo
authors.initials: V
authors.lastname: de Luca
authors.forename: Gary
authors.initials: G
authors.lastname: Remington
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
authors.forename: Albert H C
authors.initials: AH
authors.lastname: Wong
mesh_terms: D000328:Adult; D000375:Aging / Q000235:genetics; D000483:Alleles; D014150:Antipsychotic Agents / Q000009:adverse effects; D004409:Dyskinesia, Drug-Induced / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics
chemical_list: D014150:Antipsychotic Agents; C494990:GFRA2 protein, human; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors