Association between the 120-bp duplication of the dopamine D4 receptor gene and attention deficit hyperactivity disorder: genetic and molecular analyses.

Abnormalities of the dopamine neurotransmission have been hypothesized to play an important role in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Promoter variants of the dopamine D4 receptor gene (DRD4) have attracted particular interest due to their possible role in regulation of gene transcription. Here we describe the haplotype analysis of the 120 base pair duplication (120-bp dup) and three SNPs (-616C/G, -615A/G, -521C/T) in the 5' region of the DRD4 gene among children with ADHD. We observed a trend (chi(2) = 14.905, df = 9, P = 0.093) in the four-locus haplotype distribution between ADHD probands (N = 173) and controls (N = 284). The homozygote genotype of the 1-repeat form of the 120-bp dup (1-1) had a significantly higher frequency among ADHD children than in controls (8.1% vs. 3.2%, chi(2) = 5.526, df = 1, P = 0.019, Odds Ratio = 2.71). In addition, a novel, 4-repeat allele was identified among ADHD patients. This particular allele has been cloned to the luciferase expression vector and its transcriptional activity has been compared to the 1- and 2-repeat allele. The number of repeats of the 120-bp dup was found to have an effect on transcriptional activity in both neuroblastoma and retinoblastoma cell lines in a dose-dependent manner (1-repeat > 2-repeat > 4-repeat). These results suggest that the 1-repeat form of the 120-bp dup might be a risk factor of ADHD, especially in the homozygous form and/or in the context of certain haplotypes.