NEW RESEARCH
Dopamine Transporter Genotype Conveys Familial Risk of Attention-Deficit/Hyperactivity Disorder Through Striatal Activation

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ABSTRACT

Objective

The dopamine transporter (DAT1) gene has been implicated in attention-deficit/hyperactivity disorder (ADHD), although the mechanism by which it exerts its effects remains unknown. The polymorphism associated with ADHD has been shown to affect expression of the transporter in vitro and in vivo. Dopamine transporters are predominantly expressed in the striatum, but also in the cerebellar vermis. Stimulant medication is often effective in ADHD and is believed to exert its effects by blocking dopamine transporters in the striatum. We set out to investigate the effect of the DAT1 genotype in ADHD in a small, preliminary study. We hypothesized that the DAT1 genotype would affect brain activation patterns in a manner similar to that of stimulant medication, with the lesser expressing allele mirroring its effects.

Method

We investigated DAT1 gene effects on brain activation patterns in an all-male sample of sibling pairs discordant for ADHD (n = 20) and controls (n = 9). All of the subjects participated in a functional magnetic resonance imaging session using a go/no-go paradigm and provided a DNA sample for analysis.

Results

DAT1 genotype affected activation in the striatum and cerebellar vermis. The genotype interacted with familial risk of ADHD in the striatum but not the vermis.

Conclusions

These preliminary results suggest that the DAT1 gene effects in the striatum are involved in translating the genetic risk of ADHD into a neurobiological substrate. As such, this study represents a first step in elucidating the neurobiological mechanisms underlying genetic influences in ADHD. Furthermore, these results may contribute to long-term possibilities for the development of new treatments: If the DAT1 genotype has differential effects on striatal activation, then it may be useful as a surrogate endpoint in individualized treatments targeting genotype/functional magnetic resonance imaging activation profiles.

Section snippets

Subjects

A total of 29 boys, ages 11 to 20 years, participated in the present study. Sibling pairs were recruited through the University Medical Center in Utrecht, the Netherlands, whereas controls were recruited through schools in the area. All of the assessments and study participation were conducted in Dutch. All of the fMRI data included in this report were also included in a study of effects of familial risk of ADHD on brain activation patterns.18 The present study investigates genotype effects,

RESULTS

There was no effect of genotype or diagnosis on behavioral performance, nor was there an interaction between the two (F < 1.9; df = 2, 23; p >.18; n = 29).

The planned comparison of whole-brain activation for no-go trials compared to go-trials between carriers of the DAT1 9R allele (n = 13) and individuals homozygous for the 10R allele (n = 16) showed two areas that were different between groups: Activation in the striatum was greater for carriers of the 9R allele (t = 3.93, df = 28; p <.001),

DISCUSSION

We report effects of the DAT1 genotype on activation in the striatum and the vermis of the cerebellum in a small sample of subjects with ADHD and their unaffected siblings. This is consistent with previous reports of MPH effects in these regions and the pattern of DAT1 expression in the brain. We show an interaction between genotype and familial risk of ADHD for activation in the striatum, but not the cerebellar vermis. These findings should be considered preliminary given the small sample

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    This work was supported by a Dutch Science Foundation VENI grant to Dr. Durston. The authors gratefully acknowledge all of the families who participated in this study; Nick Ramsey, Arjan van der Schaaf, and Bert Heesakkers for technical support; Bas Neggers, Erno Hermans, Matthijs Vink, and Martijn van der Heuvel for SPM2 support; and the clinical team at the Disruptive Disorders Clinic for their help in subject recruitment.

    Clinical trial registration information-URL:http://www.clinicaltrials.gov. Unique identifier: NCT00143832.

    Disclosure: The authors report no conflicts of interest

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