The DRD3 Ser9Gly polymorphism and risk of dyskinesia in Parkinson's disease

Background: Beside duration and dosage of levodopa treatment, genetic predisposition contributes significantly to development of medication related complications in Parkinson's disease (PD), especially dyskinesia. So far, no genetic risk factor was established. As an important candidate, the gene of the dopamine D3 receptor (DRD3) was studied extensively in psychiatric disease, and several groups reported an association of the Ser9Gly polymorphism to antipsychotic induced tardive dyskinesia in severe mental illness. In PD, one study in a small patient sample analyzed DRD3 Ser9Gly and dyskinesia, with negative results. As recent observations, especially in animal models, strongly indicate that DRD3 participates both in dyskinesia and the therapeutic action of levodopa, we reappraised DRD3 Ser9Gly as a risk factor for development of dyskinesia in a large scale association study.

Methods: Based on the data bank of the German Kompetenznetz Parkinson, we analysed clinical information including PD symptoms and treatment complications, detailed medical history, drug therapy, and DRD3 Ser9Gly genotype in 591 patients with idiopathic PD. Known or potential risk factors for dyskinesia, namely age, gender, age of disease onset, disease duration, dopaminergic load, and DRD3 Ser9Gly genotype, were examined in a statistical risk model.

Results and Conclusions: PD patients carrying the gly variant of DRD3 Ser9Gly had a significantly higher risk of dyskinesia (p=0.004), analogous to vulnerability for tardive dyskinesia due to neuroleptic treatment in mental disease. Interestingly, no other levodopa associated complications, especially fluctuations or hallucinations, were associated to genotype or allele carrier status, underlining the hypothesis of an intrinsic predisposition for dyskinesia in PD. However, results of risk stratification are pending. Our preliminary observations will be related to age of disease onset, disease duration, and dopaminergic load, to be discussed accordingly.