title: Sequence variation in the 3'-untranslated region of the dopamine transporter gene and attention-deficit hyperactivity disorder (ADHD).
abstract: The dopamine transporter gene (DAT1) has been reported to be associated with attention-deficit hyperactivity disorder (ADHD) in a number of studies [Cook et al. (1995): Am J Human Genet 56(4):9993-998; Gill et al. (1997): Mol Psychiatry 2(4):311-313; Waldman et al. (1998): Am J Human Genet 63(6):1767-1776; Barr et al. (2001): Biol Psychiatry 49(4):333-339; Curran et al. (2001): Mol Psychiatry 6(4):425-428; Chen et al. (2003): Mol Psychiatry 8(4):393-396]. Specifically, the 10-repeat allele of the 40-bp variable number of tandem repeats (VNTR) polymorphism located in the 3' untranslated region (UTR) of the gene has been found to be associated with ADHD. There is evidence from in vitro studies indicating that variability in the repeat number, and sequence variation in the 3'-UTR of the DAT1 gene may influence the level of the dopamine transporter protein [Fuke et al. (2001): Pharmacogenomics J 1(2):152-156; Miller and Madras (2002): Mol Psychiatry 7(1):44-55]. In this study, we investigated whether DNA variation in the DAT1 3'UTR contributed to ADHD by genotyping DNA variants around the VNTR region in a sample of 178 ADHD families. These included a MspI polymorphism (rs27072), a DraI DNA change (T/C) reported to influence DAT1 expression levels, and a BstUI polymorphism (rs3863145) in addition to the VNTR. We also screened the VNTR region by direct resequencing to determine if there was sequence variation within the repeat units that could account for the association. Our results indicate that DAT1 is associated with ADHD in our sample but not with alleles of the VNTR polymorphism. We did not find any variation in the sequence for either the 10- or 9-repeat alleles in the probands screened nor did we observe the reported DraI (T/C) variation. Our results therefore refute the possibility of the reported DraI variation or alleles of the VNTR as the functional variants contributing to the disorder.
authors.affiliation: Cell and Molecular Biology Division, Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Yu
authors.initials: Y
authors.lastname: Feng
authors.forename: Karen G
authors.initials: KG
authors.lastname: Wigg
authors.forename: Rohit
authors.initials: R
authors.lastname: Makkar
authors.forename: Abel
authors.initials: A
authors.lastname: Ickowicz
authors.forename: Tejaswee
authors.initials: T
authors.lastname: Pathare
authors.forename: Rosemary
authors.initials: R
authors.lastname: Tannock
authors.forename: Wendy
authors.initials: W
authors.lastname: Roberts
authors.forename: Molly
authors.initials: M
authors.lastname: Malone
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
authors.forename: Russell
authors.initials: R
authors.lastname: Schachar
authors.forename: Cathy L
authors.initials: CL
authors.lastname: Barr
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D001483:Base Sequence; D015252:Deoxyribonucleases, Type II Site-Specific / Q000235:genetics; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D051379:Mice; D018598:Minisatellite Repeats; D008969:Molecular Sequence Data
chemical_list: D020413:3' Untranslated Regions; D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human; D015252:Deoxyribonucleases, Type II Site-Specific; C035594:TTTAAA -specific type II deoxyribonucleases