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 treate d using methylphenidate, a psychostimulant that inhibits the dopamine trans porter. This led E.H. Cook and colleagues to consider the dopamine transpor ter 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 replicat ed 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 t he 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 transmissio n of the alleles of either the VNTR or the additional two polymorphisms whe n examined individually, although there was a trend for the biased transmis sion of the 480-bp allele of the VNTR. When we examined the haplotypes of t he three polymorphisms we found significant evidence for biased transmissio n of one of the haplotypes containing the 480-bp VNTR allele, We also genot yped 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 betwee n the DAT1 gene and ADHD. Biol (C) 2001 Society of Biological Psychiatry.