DAT1 Alleles Research Articles

Association of the 480 bp DAT1 allele with methylphenidate response in a sample of Irish children with ADHD.

Several studies have implicated the dopamine transporter gene (DAT1) as conferring susceptibility to attention deficit hyperactivity disorder (ADHD), in particular, a VNTR situated at the 3' end of the gene. In addition, the 10-repeat VNTR allele associated with ADHD has been reported to be associated with an over-active transporter protein (DAT). Thus children possessing this variant might be particularly responsive to methylphenidate, a drug known to act by blocking DAT. We have examined this hypothesis and now report an association between the 10-repeat VNTR DAT1 polymorphism and retrospectively rated methylphenidate response in a sample of 119 Irish children with ADHD (chi(2) = 7.918, df = 1, P = 0.005). Our findings suggest a role for the 10-repeat DAT1 risk allele in medication response and may help to predict positive clinical outcome in ADHD.

Distribución de alelos de los genes DRD4 y DAT1 del sistema dopaminérgico en la población mixta de Santiago de Chile

Genes for dopamine receptor DRD4 and dopamine transporter DAT1 are highly polymorphic. Two alleles of these genes, namely the DRD4.7 and the DAT1*9 are frequently associated to the attention deficit disorder with hyperactivity. In Europe, the allele for DRD4 receptor with four repetitions (DRD4.4) has the highest frequency, with a median of 69%, followed by DRD4.7, with a frequency of 15%. South American indigenous populations have higher frequencies for DRD4.7 (61%) than for DRD4.4 (29%). The ten repetition allele for DAT1 transporter has a high frequency among Europeans (72%) and Amerindians (100%). The allele DAT1*9 is the second most frequent allele. To study the frequency of DRD4 and DAT1 alleles in a Chilean population sample. One hundred serum samples were obtained from blood donors in two public hospitals in Santiago. Polymorphic regions for DRD4 and DAT1 were amplified by polymerase chain reaction. The allele DRD4.4 had a frequency of 59% and DRD4.7 a frequency of 27%. The allele DAT1*10 had a frequency of 74%, followed by DAT 1*9, with a frequency of 23%. In a Chilean population sample, the frequency of DRD4 and DAT1 alleles was very similar to that of European populations.

A Quantitative Trait Locus Analysis of the Dopamine Transporter Gene in Adults with ADHD

Numerous lines of evidence have shown that attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder, whether it is considered as a category or a dimension. We tested for an association between the dopamine transporter gene (DAT1) and ADHD considering the disorder as categorical as well as a continuous trait. Genotypes for the DAT1 variable number of tandem repeat (VNTR) alleles, along with Brown Attention Deficit Disorder Scale (BADDS) and Wender Utah Rating Scale (WURS) scores were available for 152 adult ADHD patients. In 72 of these patients DNAs from at least one parent were accessible to perform a family-based analysis (FBAT). The mean quantitative trait values of the whole sample of singleton patients were compared among the specific genotype groups using ANOVA. The family-based analysis did not reveal any association between DAT1 alleles and ADHD either when it was considered as a dichotomous trait (Z = 0.16, p = .86) or as a continuous trait (Wender Scale Z = −1.67, p = .09; Brown ADD Scale Z = 0.28, p = .77). No significant differences were detected in the mean symptom scores among the specific genotype groups. The results from our study do not support a major role for the DAT1 VNTR alleles in our sample of adult ADHD. In view of several positive reports in child ADHD, more work is required to elucidate the potential role of the DAT1 VNTR as a risk factor in ADHD.

Susceptibility genes for a trait measure of attention deficit hyperactivity disorder: a pilot study in a non-clinical sample of twins

Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder, and molecular genetic studies are underway, with most researchers focusing on identifying susceptibility genes in clinical samples with ADHD. An alternative approach is to search for quantitative trait loci underlying the trait measure of ADHD in non-clinical samples. Positive findings of association of the dopamine transporter DAT1 480 bp allele (allele 10) and the DRD4 7 repeat allele with clinical ADHD have been previously reported. In this pilot study, we examined these polymorphisms in a selected population-based sample of twins (50 high scoring pairs, 42 low scoring pairs). There was a trend for an increase in the frequency of the dopamine receptor DRD4 7 repeat allele in the high-scoring concordant monozygotic twins (odds ratio=1.4). Although this result was not statistically significant, the frequency of the 7 repeat allele was similar to that reported for our clinic sample of ADHD patients drawn from the same geographical area. There was a non-significant trend for an increased frequency of the DAT1 allele 10 (odds ratio=1.3). These results suggest that a molecular genetic study based on a questionnaire-derived measure of ADHD in a non-clinical sample is feasible and the results appear to be comparable with those from studies of clinical cases. However, sample size and power are key issues to consider when using this approach.

Genetics of Childhood Disorders: XXIV. ADHD, Part 8: Hyperdopaminergic Mice as an Animal Model of ADHD

In 1937, Charles Bradley first observed that Benzedrine (amphetamine) induces a calming effect when used in hyperactive children. It is still not known how these drugs work to increase alertness in normal individuals as well as distractible and overactive children. Numerous studies have shown that psychostimulants exert their pharmacological actions through interaction with plasma membrane monoamine transporters, namely, the dopamine, serotonin, and norepinephrine transporters. The normal function of these transporters is to provide rapid removal of neurotransmitters from the synaptic cleft to permit repetitive synaptic firing. Inhibition of the transporter would prevent the normal reuptake and would lead to markedly elevated extracellular monoamine levels. Because dopamine has been strongly implicated in the control of locomotion, particular attention has been given to the interaction of these drugs with the dopamine transporter (DAT). The elevation of extracellular dopamine levels is believed to be the primary mechanism by which psychostimulants are able to regulate locomotion. This concept, as well as the proven therapeutic efficacy of psychostimulants in attention-deficit/hyperactivity disorder (ADHD) patients, has provided the basis for the hypodopaminergic hypothesis of the disorder and suggested a possible connection between DAT and ADHD. Many attempts to clarify the status of the dopamine system in patients with ADHD have been largely unsuccessful. This is generally thought to be due to the fact that many of the current approaches in clinical research, such as the analysis of plasma, urine, cerebrospinal fluid, or computer imaging techniques, provide equivocal estimates of the extracellular levels of dopamine in the major motor areas of the human brain. The hypodopaminergic hypothesis of ADHD, therefore, remains a theoretical concept inferred from an oversimplified understanding of the mechanism of action of psychostimulants in normal subjects. The hypothesized connection between DAT function and ADHD has continued to spark considerable interest. There has been a reported association between a polymorphism in the DAT gene and ADHD. Specifically, a significant association was found by Cook and associates between ADHD and the 480-bp DAT1 allele (48-bp repeat sequence). Other groups of researchers later confirmed these observations in additional cohorts of patients and concluded that the 480-bp allele of DAT1 is preferentially transmitted to ADHD probands. More recently, four different analytical strategies were used to examine the association and linkage of the DAT gene and ADHD in children. Waldman and associates replicated

The relation of the dopamine transporter gene (DAT1) to symptoms of internalizing disorders in children.

The relation of the dopamine transporter gene (DAT1) to symptoms of internalizing disorders, Tourette's disorder, and obsessive-compulsive disorder was examined using both within- and between-family tests of association. The sample consisted of clinic-referred children and their siblings and controls and their siblings. Between-family association was examined via the association of DAT1 genotypes with disorder symptoms in the population. Symptoms of all eight disorders increased with a greater number of 10-repeat DAT1 alleles. Using a quantitative transmission disequilibrium test (QTDT), linkage and within-family association was indicated by increased symptoms in children who received 10 repeat alleles from heterozygous parents relative to children who received 9 repeat alleles. Four disorders were associated with DAT1 using the QTDT: generalized anxiety, social phobia, obsessive-compulsive, and Tourette's. The effects of comorbidity were investigated by repeating the same between- and within-family analyses on residual scores, with any effects of attention deficit hyperactivity disorder symptoms removed. Although the residuals were associated less strongly with DAT1 than were the original scores, three disorders continued to show association both between and within families: generalized anxiety, Tourette's, and social phobia.