title: A common haplotype at the dopamine transporter gene 5' region is associated with attention-deficit/hyperactivity disorder.
abstract: The dopamine transporter (DAT) is the major site of methylphenidate action, which is one of the main drugs used to treat attention-deficit/hyperactivity disorder (ADHD). Most association studies with ADHD focused in a VNTR at the 3'-untranslated region of the gene (3'UTR) presenting conflicting results. However, the most common explanation to inconsistent results is variable linkage disequilibrium with an adjacent functional variant, just a few number of DAT1 studies have reported LD structure across the gene. In this study, we screened 16 polymorphisms across the DAT1 gene to understand LD structure in a Brazilian sample of families with ADHD probands and to verify if there were evidence for a biased transmission of alleles and haplotypes from parents to their 243 children with ADHD. In the DSM-IV combined subtype, we observed a preferential transmission of the haplotype A/C/C/C/A derived from five SNPs (rs2550948, rs11564750, rs261759, rs2652511, rs2975223) in 5' region (P corrected = 0.018) and no association with any allele/haplotype at the 3' region of the gene, including the 3' VNTR and the VNTR of intron 8. These results suggest a role for the promoter region in ADHD susceptibility and that allele heterogeneity should be highly considered in DAT1 gene association studies highlighting the importance of this gene in the genetics of the disorder.
authors.affiliation: Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Júlia P
authors.initials: JP
authors.lastname: Genro
authors.forename: Guilherme V
authors.initials: GV
authors.lastname: Polanczyk
authors.forename: Cristian
authors.initials: C
authors.lastname: Zeni
authors.forename: Angélica S
authors.initials: AS
authors.lastname: Oliveira
authors.forename: Tatiana
authors.initials: T
authors.lastname: Roman
authors.forename: Luis A
authors.initials: LA
authors.lastname: Rohde
authors.forename: Mara H
authors.initials: MH
authors.lastname: Hutz
mesh_terms: D020121:5' Untranslated Regions; D000293:Adolescent; D000483:Alleles; D001289:Attention Deficit Disorder with Hyperactivity / Q000175:diagnosis / Q000235:genetics*; D001938:Brazil; D002648:Child; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005091:Exons; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D009679:Nuclear Family; D010290:Parents; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
chemical_list: D020121:5' Untranslated Regions; D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human