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.

Mesocorticolimbic dopamine functioning in primary psychopathy: A source of within-group heterogeneity

“…Some studies that examine DAT1 mRNA levels in vitro report that the 10R-allele expresses higher levels of protein material when prompted (Fuke et al, 2001;Mill et al, 2002;VanNess et al, 2005;Kanno and Ishiura, 2012), while others report higher expression in the 9R-allele (Michelhaugh et al, 2001;Miller and Madras, 2002), and others still, find no significant differences (Greenwood and Kelsoe, 2003). However, in vivo studies with healthy subjects consistently report higher DAT densities in 9R-carriers (Jacobsen et al, 2000;Van Dyck et al, 2005;Van de Giessen et al, 2009;Costa et al, 2011;Shumay et al, 2011;Spencer et al, 2013), whereas those in psychiatric patients with schizophrenia, ADHD, or substance dependence, report higher DAT densities in 10R-homozygotes (e.g. Heinz The common denominator in subjects with schizophrenia, ADHD, and substance abuse is that these conditions are characterized by pathological dysregulations of neuronal DA levels in mesolimbic projections (Stahl, 2008).…”

Amphetamine-Induced Dopamine Release and Neurocognitive Function in Treatment-Naive Adults with ADHD

“…For example, both increases and decreases have been reported for D 2 /D 3 receptor availability and for dopamine transporter (DAT) binding in ADHD patients vs controls (Lou et al, 2004;Spencer et al, 2005;Spencer et al, 2013;Volkow et al, 2007a;Volkow et al, 2009). Only one study has examined DA release in untreated ADHD (Volkow et al, 2007b).…”

Dopamine transporter gene susceptibility to methylation is associated with impulsivity in nonhuman primates

“…The presence of the 10-repeat allele (10R) has been correlated with the occurrence of attention deficit hyperactivity disorder (ADHD; Cook et al 1995;Gill et al 1997;Waldman et al 1998;Daly et al 1999;Winsberg and Comings 1999), of which impulsivity is a cardinal symptom. In addition, greater DAT availability in the striatum has been associated with ADHD (Dougherty et al 1999;Dresel et al 2000;Krause et al 2000;Larish et al 2006), impulsivity (Costa et al 2013), and the 10R (Heinz et al 2000) and 9R (Jacobsen et al 2000;Spencer et al 2013) alleles of the DAT VNTR.…”

“…While these correlations suggest that alterations in the DAT gene or its expression mediate impulsive behavior, a direct link has not been established (Spencer et al 2013;Miller and Madras 2002;Miller et al 2001). For instance, the 10R allele, which is associated with ADHD, is more common in the general population than is the incidence of ADHD (Mitchell et al 2000).…”