Dopamine Transporter Genotype Conveys Familial Risk of Attention-Deficit/Hyperactivity Disorder Through Striatal Activation
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.
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Some promising initial evidence has indicated that the DAT1 3′UTR polymorphism may be modulating the responsivity of the striatum during a response inhibition and a reward-processing paradigm.
“Some promising initial evidence has indicated that the DAT13′UTR polymorphism may be modulating the responsivity of the striatum during a response inhibition and a reward-processing paradigm (Durston et al, 2008; Forbes et al, 2009).”
From DAT1 and COMT effects on delay discounting and trait impulsivity in male adolescents with attention deficit/hyperactivity disorder and healthy controls (2010) · cites this paper as Durston et al, 2008
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- Authors
- DURSTON, S., FOSSELLA, J. A., MULDER, M. J., CASEY, B. J., ZIERMANS, T. B., VESSAZ, M. N., & VAN ENGELAND, H.
- Affiliations
- Mount Sinai Hospital (US)
- Corresponding author
- DURSTON, SARAH
- Venue
- Journal of the American Academy of Child & Adolescent Psychiatry
- Publisher
- Elsevier BV
- Published
- 2008-01
- Volume
- 47
- Issue
- 1
- Pages
- 61-67
- ISSN
- 0890-8567 (ISSN-L)
- OpenAlex
- W2049369777
- Cited by
- 108
- References
- 33
- Citations by year
- 2022: 2 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 4 · 2017: 4 · 2016: 5 · 2015: 7 · 2014: 10 · 2013: 6 · 2012: 10
- FWCI
- 12.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the American Academy of Child & Adolescent Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- dopamine transporter, DAT1 gene, attention deficit hyperactivity disorder, familial risk, striatum, cerebellar vermis, brain activation, go/no-go task, stimulant medication, genotype-phenotype interaction, genetic risk, personalized treatment
- MeSH terms
- Adolescent, Adult, Alleles, Attention Deficit Disorder with Hyperactivity, Brain Mapping, Cerebellum, Child, Corpus Striatum, Genotype, Genetic Carrier Screening, Humans, Magnetic Resonance Imaging, Male, Risk, Gene Expression, Minisatellite Repeats, Dopamine Plasma Membrane Transport Proteins
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