Haplotype study of three polymorphisms at the dopamine transporter locus confirm linkage to attention-deficit/hyperactivity disorder.
BACKGROUND
Attention-deficit/hyperactivity disorder (ADHD) is often treated using methylphenidate, a psychostimulant that inhibits the dopamine transporter. This led E.H. Cook and colleagues to consider the dopamine transporter locus (DAT1) as a primary candidate gene for ADHD. That group reported a significant association between ADHD and the 480-base pair (bp) allele of the variable number of tandem repeats (VNTR) polymorphism located in the 3' untranslated region of the DAT1 gene. This association was later replicated in additional studies.


METHODS
The DAT1 gene has additional common polymorphisms in intron 9 and exon 9. We investigated the possibility of linkage of DAT1 and ADHD using the VNTR polymorphism and two additional common polymorphisms in 102 nuclear families with an ADHD proband. Using the transmission disequilibrium test, we examined the transmission of the alleles of each of these polymorphisms, as well as the haplotypes of the polymorphisms.


RESULTS
We did not observe significant evidence for the biased transmission of the alleles of either the VNTR or the additional two polymorphisms when examined individually, although there was a trend for the biased transmission of the 480-bp allele of the VNTR. When we examined the haplotypes of the three polymorphisms we found significant evidence for biased transmission of one of the haplotypes containing the 480-bp VNTR allele. We also genotyped six additional DNA sequence variants of the DAT1 gene. However, these variants were not sufficiently polymorphic in our sample to be informative. Two of the DNA variants that result in an amino acid change, Ala559Val and Glu602Gly, were not observed in our sample.


CONCLUSIONS
Our results support previous findings of an association between the DAT1 gene and ADHD.
Department of Psychiatry, The Toronto Western Hospital, Toronto, Canada.
C L
CL
Barr
C
C
Xu
J
J
Kroft
Y
Y
Feng
K
K
Wigg
G
G
Zai
R
R
Tannock
R
R
Schachar
M
M
Malone
W
W
Roberts
M M
MM
Nöthen
F
F
Grünhage
D J
DJ
Vandenbergh
G
G
Uhl
G
G
Sunohara
N
N
King
J L
JL
Kennedy
D000483:Alleles; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D001693:Biological Transport, Active / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D004298:Dopamine / Q000235:genetics* / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D005091:Exons; D008040:Genetic Linkage; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D018598:Minisatellite Repeats / Q000235:genetics*; D009419:Nerve Tissue Proteins; D011110:Polymorphism, Genetic / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins
D002352:Carrier Proteins; C060858:DAT1 protein, S cerevisiae; D004268:DNA-Binding Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493214:SLC6A3 protein, human; D029701:Saccharomyces cerevisiae Proteins; D004298:Dopamine