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

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Abstract

Objective

To examine genetic associations of polymorphisms in the dopamine receptor D2 (DRD2) and D3 (DRD3) genes with risk of Parkinson's disease (PD).

Methods

The study included 1325 newly diagnosed patients with PD and 1735 controls from a consortium of five North American case–control studies. We collected risk factor information by in-person or telephone interview. Six DRD2 and two DRD3 polymorphisms were genotyped using a common laboratory. Odds ratios were estimated using logistic regression.

Results

Among non-Hispanic whites, homozygous carriers of Taq1A DRD2 (rs1800497) polymorphism had an increased risk of PD compared to homozygous wildtype carriers (OR = 1.5, 95% CI 1.0–2.3). In contrast, the direction of association for Taq1A polymorphism was opposite for African–Americans, showing an inverse association with PD risk (OR = 0.10, 95% CI 0.2–0.7). Among white Hispanics who carried two alleles, the Ser9Gly DRD3 (rs6280) polymorphism was associated with a decreased risk of PD (OR = 0.4, 95% CI 0.2–0.8). The inverse association of smoking with PD risk was not modified by any of the DRD2 or DRD3 polymorphisms.

Conclusions

DRD2 polymorphisms are unlikely to be true disease-causing variants; however, three DRD2 polymorphisms (including Taq1A) may be in linkage disequilibrium with possible disease associated variants in the DRD2-ANKK1-NCAM1-TTC12 gene cluster.

Introduction

Genetic polymorphisms of the dopamine D2 receptor (DRD2) and D3 receptor (DRD3) genes may be associated with PD, either due to their influence on dopamine regulation [1] or to their association with cigarette smoking, which is inversely related to the risk of PD [2]. Numerous association studies have reported that the DRD2 Taq1A polymorphism is associated with taking up the smoking habit, with earlier onset and current smoking, and with fewer attempts to quit smoking [1]. However, two recent meta-analyses of the effect of DRD2 polymorphisms on smoking behavior reported conflicting results, with one study reporting a higher prevalence of Taq1A allele in smokers [3], and the other finding no association of DRD2 polymorphisms with any measures of smoking [4].

Several case–control studies have investigated the association of certain polymorphisms in DRD2 and DRD3 genes with PD, with varying results [5], [6], [7], [8], [9], [10], [11], [12], [13]. None of these studies assessed whether dopamine receptor polymorphisms modify the influence that smoking has on PD risk. To address these disparate results, we investigated whether polymorphisms in the DRD2 and DRD3 genes are associated with PD and whether they modify the association of smoking with risk of PD in a large multiethnic consortium study.

Section snippets

Study design and populations

We created a research consortium, Parkinson's Epidemiology and Genetics Association Studies in the US (PEGASUS), which combined DNA and risk factor data from five epidemiologic studies of PD, two of which were nested within a cohort study [14], [15], [16], [17], [18], [19]. Table 1 summarizes the characteristics of the study populations including the research diagnostic criteria for PD [20], [21].

Data collection methods

Professional interviewers conducted structured clinic, in-home or telephone interviews to collect

Results

The cases and controls differed with respect to age, race/ethnicity, family history of PD and smoking status. The case group was slightly younger and had a higher proportion of non-Hispanic whites (Table 3); however, these variables were controlled for in the analysis. Cases were more likely to have a family history of PD and were less likely than controls to have been ever smokers or to be current smokers.

We examined Hardy–Weinberg equilibrium (HWE) within each ethnic group within each site

Discussion

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

Acknowledgments

Funding was provided to the PEGASUS genetic consortium by the Michael J. Fox Foundation for Parkinson's Research. Additional funding to individual investigators for the original studies was provided by: NIH NS R01-31964, NIH ES R03-13970, and Tobacco-Related Disease Research Fund Grants 8RT-0131 and 11RT-0237 (Dr. Lorene Nelson,); NIH R01-NS32527 (Drs. Richard Mayeux and Karen Marder), NIAPO1 AG07232 (Dr. Richard Mayeux); NIH ES10544 and U54-ES12078, pilot funding from SCEHSC # 5P30 ES07048,

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    1

    Current address: Department of Infectious Diseases, Stanford University School of Medicine, Stanford, CA, USA.

    2

    Current Address: Hudson Alpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, USA.

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