In the PEGASUS multiethnic consortium, we observed significant associations of three DRD2 polymorphisms with the risk of PD (Taq1A, rs6279, −141CIns/Del). Taq1A was positively associated with PD in non-Hispanic Caucasians and inversely associated with PD in other racial and ethnic groups. Among African American subjects, we noted significant positive associations for two other DRD2 polymorphisms (rs6279, −141CIns/Del).
Non-Hispanic whites who carried two Taq1A alleles had a 50% increased risk of PD, replicating associations observed in three recent PD studies conducted in non-Hispanic white populations. One large study conducted in five European centers (767 cases, 1989 controls) reported an OR of 1.4 for homozygous carriers of the Taq1A DRD2
polymorphism (95% CI 1.0–2.0) [11
]. Significant positive associations were also observed in a study of Norwegians (homozygous Taq1A OR=2.2, 95% CI 1.1–4.4) [7
] and a study of Italians (among carriers of at least one Taq1A allele, OR=1.7, 95% CI 1.1–2.7) [6
]. Although two other smaller studies found no association of the Taq1A SNP with PD risk [5
], the preponderance of evidence strongly supports an association between Taq1A homozygosity and PD risk among non-Hispanic white subjects. PDGene database allows a meta-analysis of the association of the Taq1A DRD2
allele and risk of PD [24
]. The allelic association of DRD2
Taq1A was 1.1 (95% CI 0.96–1.2) [24
], indicating that a genotypic analysis is essential for identifying the specific association of the DRD2
homozygous state with PD.
In contrast to the finding of a positive association of Taq1A homozygosity and PD risk among non-Hispanic whites, we found that African Americans who carried one or two Taq1A alleles had a significant 80%–90% decreased risk for PD. Similarly, Asian and Hispanic carriers of the Taq1A allele were at decreased risk for PD, but the results were not statistically significant. The sample sizes in these ethnic groups were relatively small; therefore our results need replication in future studies. 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.
In our study, we did not find an association of DRD2
−141CIns/Del polymorphism with PD among non-Hispanic whites or Asians, a finding similar to those of two other case-control studies, one in a non-Hispanic white population [7
] and another in India [9
]. However, African-Americans in PEGASUS had a nearly four-fold increase in risk of PD if they carried one or two alleles of the DRD2
−141 Ins/Del polymorphism, and a thirteen-fold increase in risk of PD if they carried one or two alleles of the rs6279 polymorphism.
Of note is that the minor allele frequencies (MAF) of DRD2
SNPs vary widely among racial/ethnic groups. In our study, the prevalence of the DRD2
-141 Ins/Del polymorphism was much higher in African Americans (57% of cases, 39% of controls) compared to the other racial groups. Gelernter et al. [25
] noted a similar result in community volunteer subjects where the MAF for the −141CIns/Del polymorphism was 39% for African Americans, compared to 11% for non-Hispanic whites and 21% for Japanese Americans.
Together these findings suggest that Taq1A is unlikely to be a true disease-causing variant, but that Taq1A and other DRD2
polymorphisms (particularly among African Americans) may be in linkage disequilibrium with possible disease associated variants. Taq1A actually resides in the coding region of a neighboring gene ANKK1
(ankyrin repeats and kinase domaine containing 1 gene) approximately 10 kb downstream of DRD2
is a serine/threonine kinase involved in signal transduction, thought to affect dopaminergic reward processes [26
], and is located with a cluster of genes, which includes not just DRD2
, but neural cell adhesion molecule 1 (NCAM1
) and tetratricopeptide repeat domain 12 (TTC12
]. In this gene cluster, DRD2
maps molecularly close to NCAM1
, and both are functional candidates for Alzheimer’s disease risk [27
Taq1A polymorphism has been associated with the propensity to engage in addictive behaviors including cigarette smoking [1
]. Gelernter et al. [28
] reported a strong association between a haplotype spanning TTC12
and nicotine dependence, in both non-Hispanic white and African American populations. Although DRD2
Taq1A was not associated with nicotine dependence, the authors noted that two of the four SNPS selected for haplotype analysis were in linkage disequilibrium with DRD2
]. Huang et al. [29
] also noted a significant association between a functional polymorphism in ANKK1
and nicotine dependence in African-Americans. In PEGASUS, we examined the relation between smoking and the Taq1A polymorphism in control subjects and found no association with any of the cigarette smoking measures. Nor did the Taq1A polymorphism modify the smoking-PD association in our study in any of the racial/ethnic groups. All four of these genes in the ANKK1
cluster are considered candidate loci for substance dependence [28
], and complexities of this genomic region may explain the inconsistency in DRD2
associations with nicotine dependence across studies. The three other genes in this cluster have not been taken into consideration in our study nor in other previous studies of PD. Given the consistent finding of an inverse association between smoking and PD, future genetic association studies with markers in this four-gene cluster with PD could be fruitful.
genetic polymorphisms (rs6280 and rs2134655) were not associated with PD risk in most racial/ethnic groups. The only significant result was a 60% decrease in risk for PD among Hispanic white subjects who carried two polymorphisms for Ser9Gly (rs6280), a nonsynomous coding region variant. Other case-control studies have found no association between this polymorphism and PD [9
], none of which included Hispanic populations. When we examined the smoking and PD association, none of the DRD3
polymorphisms modified the effect of smoking. The Ser9Gly (rs6280) polymorphism lies within the region not thought to be involved with ligand binding or signal transduction [30
]. Thus, the variant may itself be functional or may be in linkage disequilibrium with other markers involved in susceptibility to PD and other neurologic conditions.
Our consortium study has a number of strengths, including (a) the methodologic rigor of the individual studies, (b) the large number of well characterized PD patients, most of whom have newly diagnosed PD, (c) the quality and comparability of information on tobacco exposure and (d) a greater degree of racial/ethnic diversity of subjects than any one study can usually provide. However, we did not have sufficient numbers of individuals other than non-Hispanic whites to provide precise odds ratio estimates for any of the groups. The significant associations noted in racial/ethnic groups other than white non-Hispanics may also be a reflection of population admixture.
The results of this study warrant further research in order to gain an understanding of the role that DRD2 and DRD3, and other genes in the DRD2 genomic region, might play in the etiology of PD. Future studies of genetic associations will greatly benefit from the inclusion of sufficiently large numbers of individuals in racial and ethnic groups other than Caucasians and better characterisation of the DRD2-ANKK1-NCAM1-TTC12 gene cluster.