Functional genomics of attention-deficit/hyperactivity disorder (adhd) risk alleles on dopamine transporter binding in ADHD and healthy control subjects

Thomas J. Spencer*, Joseph Biederman, Stephen V. Faraone, Bertha K. Madras, Ali A. Bonab, Darin D. Dougherty, Holly Batchelder, Allison Clarke, Alan J. Fischman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)84-89
Number of pages6
JournalBiological psychiatry
Volume74
Issue number2
DOIs
StatePublished - Jul 15 2013

Keywords

  • ADHD
  • PET imaging
  • altropane
  • dopamine
  • dopamine transporter
  • genetics

ASJC Scopus subject areas

  • Biological Psychiatry

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