Dopaminergic polymorphisms in Tourette syndrome: association with the DAT gene (SLC6A3).

Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by involuntary motor and phonic tics. The pattern of inheritance and associated genetic abnormality has yet to be fully characterized. A dopaminergic abnormality in this disorder is supported by response to specific therapies, nuclear imaging, and postmortem studies. In this protocol, dopaminergic polymorphisms were examined for associations with TS and attention-deficit hyperactivity disorder (ADHD). Polymorphisms investigated included the dopamine transporter (DAT1 DdeI and DAT1 VNTR), dopamine receptor (D4 Upstream Repeat and D4 VNTR), dopamine converting enzyme (dopamine beta-hydroxylase), and the acid phosphatase locus 1 (ACP1) gene. DNA was obtained from 266 TS individuals +/- ADHD and 236 controls that were ethnicity-matched. A significant association, using a genotype-based association analysis, was identified for the TS-total and TS-only versus control groups for the DAT1 DdeI polymorphism (AG vs. AA, P = 0.004 and P = 0.01, respectively). Population structure, estimated by the genotyping of 27 informative SNP markers, identified 3 subgroups. A statistical re-evaluation of the DAT1 DdeI polymorphism following population stratification confirmed the association for the TS-total and TS-only groups, but the degree of significance was reduced (P = 0.017 and P = 0.016, respectively). This study has identified a significant association between the presence of TS and a DAT polymorphism. Since abnormalities of the dopamine transporter have been hypothesized in the pathophysiology of TS, it is possible that this could be a functional allele associated with clinical expression.