Genetic susceptibility to Parkinson’s disease among South and North Indians: I. Role of polymorphisms in dopamine receptor and transporter genes and association of DRD4 120-bp duplication marker

Abstract

The depletion of dopamine levels in the brain due to degeneration of dopaminergic neurons of substantia nigra pars compacta is a hallmark of Parkinson's disease (PD). The cumulative contribution of genetic variations in genes from the dopaminergic pathway has been widely implicated to confer susceptibility to idiopathic PD. We present in this paper an extensive association analysis of a total of 20 markers including single nucleotide polymorphism/short tandem repeat/variable number tandem repeat/duplication markers from five candidate genes (namely, dopamine receptors DRD1, DRD2, DRD3, and DRD4, and dopamine transporter) with PD among two independent sample sets. The allelic, genotypic, and haplotypic association of these markers with PD was tested in South Indian (SI) samples (147 cases, 130 controls) and replicated in a larger North Indian (NI) sample set (340 cases, 344 controls). Of the several markers analyzed, 120 bp duplication marker of DRD4 gene showed promising results with PD in both of the sample sets. A significant allelic association in SI [odds ratio, OR (95% confidence interval, CI)=0.67 (0.47-0.97) for 120 bp dup; 1.48 (1.03-2.13) for 120 bp WT] and genotypic association in SI [OR (95% CI)= 0.56 (0.35-0.91) for 120 bp dup/dup; 1.62 (0.99-2.64) for 120 bp dup/120 bp WT] and in NI [OR (95% CI)= 1.41 (1.03-1.93) for 120 bp dup/120 bp WT] was observed. This is the first report on the association of dopaminergic gene polymorphisms with PD from the Indian sub-continent.

Association of DRD2 and DRD3 polymorphisms with Parkinson's disease in a multiethnic consortium

“…Ours is the first study to include African Americans, but three other studies have examined the association of Taq1A and PD risk in Asian populations. Singh et al reported a decreased risk in PD among those who were homozygous for the Taq1A polymorphism (OR=0.3, 95% CI 0.1–1.0) [12], while another study in India [9] and one in Singapore [8] found no association.…”

Movement disorders: Indian scenario: A clinico-genetic review

“…[45] In India, candidate gene studies have been performed on SNCA, [46,47] Parkin, [48][49][50][51][52] PINK1, [53] DJ-1, [54,55] and LRRK2 [47,[56][57][58][59] only [ In India studies to understand the molecular basis of PD is rapidly getting pace. A number of association studies have been reported on the candidate [53,60] as well as the susceptibility genes involved in dopamine metabolism, [61][62][63] xenobiotic metabolism, [64,65] neuronal cytoskeletal stability [66,67] etc., from different parts of India. Recent genome wide association studies on Asian and Caucasian populations have identified a number of associated genes in PD including ethnicity specific susceptible genes.…”

SLC6A3 is a risk factor for Parkinson's disease: A meta-analysis of sixteen years’ studies

“…After estimation of statistic power, a variable number of tandem repeat located in 3′untranslated region (3′VNTR) and four SNPs (rs6347, rs3756450, rs2652510, rs2550956) were included in current combined-analysis, as listed in Table 1 [5,7,13,16,18–20,22–27,31,33–36,38–40,46,48,49]. There was lack of power for combined-analysis of other SLC6A3 polymorphisms.…”

“…Studies with 3′VNTR have revealed some associations with the risk for PD. However, the association results have been conflicted [13,16,19,20,22–24,26,27,33,36,38]. The confliction may underscore ethnic differences and poor power of detection in individual samples especially when the genetic effect is small.…”