Dopamine transporter genotype conveys familial risk of attention-deficit/hyperactivity disorder through striatal activation.
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.


METHODS
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.
Durston
Sarah
S
Drs. Durston, Mulder, Ziermans, Vessaz, and Van Engeland are with the Department of Child and Adolescent Psychiatry, Rudolf Magnus Institute for Neurosciences; Drs. Casey and Durston are with the Sackler Institute for Developmental Psychobiology; and Dr. Fossella is with Mount Sinai Hospital, New York. Electronic address: S.Durston@umcutrecht.nl.
Fossella
John A
JA
Drs. Durston, Mulder, Ziermans, Vessaz, and Van Engeland are with the Department of Child and Adolescent Psychiatry, Rudolf Magnus Institute for Neurosciences; Drs. Casey and Durston are with the Sackler Institute for Developmental Psychobiology; and Dr. Fossella is with Mount Sinai Hospital, New York.
Mulder
Martijn J
MJ
Drs. Durston, Mulder, Ziermans, Vessaz, and Van Engeland are with the Department of Child and Adolescent Psychiatry, Rudolf Magnus Institute for Neurosciences; Drs. Casey and Durston are with the Sackler Institute for Developmental Psychobiology; and Dr. Fossella is with Mount Sinai Hospital, New York.
Casey
B J
BJ
Drs. Durston, Mulder, Ziermans, Vessaz, and Van Engeland are with the Department of Child and Adolescent Psychiatry, Rudolf Magnus Institute for Neurosciences; Drs. Casey and Durston are with the Sackler Institute for Developmental Psychobiology; and Dr. Fossella is with Mount Sinai Hospital, New York.
Ziermans
Tim B
TB
Drs. Durston, Mulder, Ziermans, Vessaz, and Van Engeland are with the Department of Child and Adolescent Psychiatry, Rudolf Magnus Institute for Neurosciences; Drs. Casey and Durston are with the Sackler Institute for Developmental Psychobiology; and Dr. Fossella is with Mount Sinai Hospital, New York.
Vessaz
M Nathalie
MN
Drs. Durston, Mulder, Ziermans, Vessaz, and Van Engeland are with the Department of Child and Adolescent Psychiatry, Rudolf Magnus Institute for Neurosciences; Drs. Casey and Durston are with the Sackler Institute for Developmental Psychobiology; and Dr. Fossella is with Mount Sinai Hospital, New York.
VAN Engeland
Herman
H
Drs. Durston, Mulder, Ziermans, Vessaz, and Van Engeland are with the Department of Child and Adolescent Psychiatry, Rudolf Magnus Institute for Neurosciences; Drs. Casey and Durston are with the Sackler Institute for Developmental Psychobiology; and Dr. Fossella is with Mount Sinai Hospital, New York.
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000503:physiopathology; D001931:Brain Mapping; D002531:Cerebellum / Q000503:physiopathology; D002648:Child; D003342:Corpus Striatum / Q000503:physiopathology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D015870:Gene Expression / Q000502:physiology; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics; D012306:Risk
D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human