Genetic susceptibility to tardive dyskinesia among schizophrenia subjects: IV. Role of dopaminergic pathway gene polymorphisms.
OBJECTIVE
Tardive dyskinesia (TD) is an antipsychotic induced side effect observed in 20-30% of schizophrenia subjects on long-term typical antipsychotic treatment. We tested the possible association of 24 polymorphisms from six dopaminergic genes: namely, dopamine receptors D1, D2, D3, D4; the dopamine transporter (DAT); and the catalyzing enzyme catechol-O-methyltransferase (COMT), with TD.


METHODS
Multiple SNP/VNTR markers from candidate genes were analyzed using suitable approaches and allelic, genotypic and haplotypic associations were tested.


RESULTS
120 bp duplication marker, 1.2 kb upstream from initiation codon of DRD4 gene showed a significant genotypic association [chi2 = 9.29, P = 0.009; OR (95% CI) = 0.52 (0.31-0.86) for genotype 120 dup/120 dup]. In the COMT gene, a significant allelic [chi2 = 13.87, P = 0.0002] as well as genotypic association [chi2 = 16.08, P = 0.0003; OR (95% CI) = 0.24 (0.11-0.55) for genotype GG] was observed with the 408 C>G (exon 4) single nucleotide polymorphism and a significant genotypic association [chi2 = 6.32, P = 0.04; OR (95% CI) = 0.50 (0.33-0.92) for genotype GG] was observed with 472 G > A (exon 4, Val 158 Met) SNP. 120 bp dup-T-repeat 3 in DRD4 and G-C-A-insC in COMT genes were observed to be TD associated haplotypes.


CONCLUSIONS
Our study presents a detailed analysis of the possible role of dopaminergic genes in the genesis of TD. DRD4 and COMT genes were observed to be the most important candidates in North Indian schizophrenia subjects. These suggestive associations need to be investigated in replicate studies.
Srivastava
Vibhuti
V
Department of Genetics, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110 021, India.
Varma
Panchami G
PG
Prasad
Suman
S
Semwal
Prachi
P
Nimgaonkar
Vishwajit L
VL
Lerer
Bernard
B
Deshpande
Smita N
SN
BK
Thelma
T
D002394:Catechol O-Methyltransferase / Q000235:genetics*; D004409:Dyskinesia, Drug-Induced / Q000150:complications* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008957:Models, Genetic; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D017447:Receptors, Dopamine D1 / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics; D050637:Receptors, Dopamine D3 / Q000235:genetics; D050638:Receptors, Dopamine D4 / Q000235:genetics*; D012559:Schizophrenia / Q000150:complications* / Q000235:genetics*
D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D002394:Catechol O-Methyltransferase