Genetic susceptibility to tardive dyskinesia among schizophrenia subjects: IV. Role of dopaminergic pathway gene polymorphisms

Abstract

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 [χ ²=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 [χ²=13.87, P=0.0002] as well as genotypic association [χ²=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 [χ²=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.