Glial cell line-derived neurotrophic factor receptor alpha 2 (GFRA2) gene is associated with tardive dyskinesia.
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.
Souza
Renan P
RP
Neurogenetics Section, Neuroscience Department, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
de Luca
Vincenzo
V
Remington
Gary
G
Lieberman
Jeffrey A
JA
Meltzer
Herbert Y
HY
Kennedy
James L
JL
Wong
Albert H C
AH
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
D014150:Antipsychotic Agents; C494990:GFRA2 protein, human; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors