title: Functional genomics of attention-deficit/hyperactivity disorder (ADHD) risk alleles on dopamine transporter binding in ADHD and healthy control subjects.
abstract: BACKGROUND
  The main aim of this study was to examine the relationship between dopamine transporter (DAT) binding in the striatum in individuals with and without attention-deficit/hyperactivity disorder (ADHD), attending to the 3'-untranslated region of the gene (3'-UTR) and intron8 variable number of tandem repeats (VNTR) polymorphisms of the DAT (SLC6A3) gene.
  
  
  METHODS
  Subjects consisted of 68 psychotropic (including stimulant)-naïve and smoking-naïve volunteers between 18 and 55 years of age (ADHD n = 34; control subjects n = 34). Striatal DAT binding was measured with positron emission tomography with 11C altropane. Genotyping of the two DAT (SLC6A3) 3'-UTR and intron8 VNTRs used standard protocols.
  
  
  RESULTS
  The gene frequencies of each of the gene polymorphisms assessed did not differ between the ADHD and control groups. The ADHD status (t = 2.99; p<.004) and 3'-UTR of SLC6A3 9 repeat carrier status (t = 2.74; p<.008) were independently and additively associated with increased DAT binding in the caudate. The ADHD status was associated with increased striatal (caudate) DAT binding regardless of 3'-UTR genotype, and 3'-UTR genotype was associated with increased striatal (caudate) DAT binding regardless of ADHD status. In contrast, there were no significant associations between polymorphisms of DAT intron8 or the 3'-UTR-intron8 haplotype with DAT binding.
  
  
  CONCLUSIONS
  The 3'-UTR but not intron8 VNTR genotypes were associated with increased DAT binding in both ADHD patients and healthy control subjects. Both ADHD status and the 3'-UTR polymorphism status had an additive effect on DAT binding. Our findings suggest that an ADHD risk polymorphism (3'-UTR) of SLC6A3 has functional consequences on central nervous system DAT binding in humans.
authors.affiliation: Pediatric Psychopharmacology Unit, Boston, Massachusetts 02114, USA. tspencer@partners.org
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Spencer
authors.forename: Joseph
authors.initials: J
authors.lastname: Biederman
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.forename: Bertha K
authors.initials: BK
authors.lastname: Madras
authors.forename: Ali A
authors.initials: AA
authors.lastname: Bonab
authors.forename: Darin D
authors.initials: DD
authors.lastname: Dougherty
authors.forename: Holly
authors.initials: H
authors.lastname: Batchelder
authors.forename: Allison
authors.initials: A
authors.lastname: Clarke
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Fischman
mesh_terms: D020413:3' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000483:Alleles; D001289:Attention Deficit Disorder with Hyperactivity / Q000000981:diagnostic imaging / Q000235:genetics*; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D011110:Polymorphism, Genetic; D011877:Radionuclide Imaging; D012307:Risk Factors; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; D050483:Dopamine Plasma Membrane Transport Proteins; C102282:N-iodoallyl-2-carbomethoxy-3-(4-fluorophenyl)tropane; C493214:SLC6A3 protein, human; D003042:Cocaine