Association study of a dopamine transporter polymorphism and attention deficit hyperactivity disorder in UK and Turkish samples

Abstract

Molecular genetic studies in attention deficit hyperactivity disorder (ADHD) have focussed on candidate genes within the dopamine system, which is thought to be the main site of action of stimulant drugs, the primary pharmacological treatment of the disorder. 1 Of particular interest are findings with the dopamine transporter gene (DAT1), since stimulant drugs interact directly with the transporter protein.2,3 To date, there have been eight published association studies of ADHD with a 480 basepair allele of a variable number tandem repeat (VNTR) polymorphism in the 3Ј-untranslated region of the gene, five 4-8 that support an association and three 9-11 against. We have analysed the same VNTR marker in a dataset of UK Caucasian children and an independent dataset of Turkish Caucasian children with DSM-IV ADHD, using the transmission disequilibrium test (TDT).12 Results from the UK ( In this study, we have taken a family-based association design to investigate the DAT1 VNTR marker in a dataset of UK Caucasian children and an independent dataset of Turkish Caucasian children. Cases were included if they had a diagnosis of ADHD under DSM-IV criteria and DNA from both parents available for genotyping. They were excluded if they had neurological disease or damage or congenital disorders known to cause hyperactivity. The UK sample consisted of 59 cases with the combined subtype, six the hyperactive/impulsive subtype and one the inattentive subtype of ADHD. Axis 1 co-morbidity other than oppositional defiant disorder and conduct disorder (ODD/CD) consisted of two cases with an affective disorder. The Turkish sample consisted of 111 complete trios with DSM-IV-ADHD combined type. Comorbid diagnoses other than ODD/CD were Tourette's syndrome and/or tics (TS/tics) in 34% and anxiety/depression in 8% of probands.Analysis was performed using the transmission disequilibrium test (TDT) of linkage in the presence of association.12 In order to further evaluate the evidence, we included data from other published reports and performed a combined analysis. The results of this study are shown in Table 1. When considered alone, data from the UK sample ( 2 = 6.12, P = 0.0.01, OR = 1.95), but not the Turkish sample ( 2 = 0.93, P = 0.335), support association and linkage between the DAT1 locus and ADHD.We are not alone in finding differences between datasets. Among previous published reports there have been five providing evidence for the association and three against. The reasons for this are unclear and require further investigation, but may relate to the statistical power of individual samples. To address this issue we combined available published data on the VNTR polymorphism and applied the TDT. Because the TDT is primarily a test of linkage, it is valid to analyse the combined data by adding the number of transmitted and non-transmitted alleles across different studies. As shown in Table 1, combined analysis provides evidence for association and linkage at an alphalevel of 0.06 and odds ratio of 1.15. Although diagnostic differences...

Dopamine Transporter (SLC6A3) Genotype Impacts Neurophysiological Correlates of Cognitive Response Control in an Adult Sample of Patients with ADHD

“…In summary, our findings are in accordance with studies favoring the nine-repeat allele as a risk allele for ADHD in adults (van Dyck et al, 2005;Franke et al, 2008Franke et al, , 2010, but not with studies favoring the 10-repeat allele that seems to be the risk allele for ADHD in children (Chen et al, 2003;Cook et al, 1995;Curran et al, 2001). Here the nine-repeat allele was associated with abnormalities in cognitive response control and related cortical activation in ADHD patients.…”

Functional polymorphisms in dopamine and serotonin pathway genes

“…Studies with this marker led to the implication of SLC6A3 in ADHD, with the first genetic study showing a significant association between the disorder and the 10-repeat allele (P 5 0.006) [Cook et al, 1995]. Subsequently several research groups replicated this finding in different clinical samples with overall P-values ranging from 0.01 to 0.001 [Gill et al, 1997;Waldman et al, 1998;Daly et al, 1999;Barr et al, 2001;Curran et al, 2001;Chen et al, 2003]. Faraone et al [2005] recently evaluated the evidence for the association of the 3 0 UTR with ADHD, and on the basis of the pooled odds ratio (OR) across studies, found a small but statistically significant OR in favor of this association.…”

Dopaminergic System Genes in ADHD Toward a Biological Hypothesis

“…Cook et al (1995) reported an association between the 480bp DAT1 allele, one of the common alleles of a 40bp repeat situated in the 3 Ј untranslated region of the DAT1 gene which maps to 5p15.3 and ADHD. Since then, this finding has been replicated by our group (Gill et al 1997;Daly et al 1999), Waldman et al (1998), andCurran et al (2001) (in a UK sample), but not by others (Asherson et al 1998;Palmer et al 1999;Holmes et al 2000;and Roman et al 2001). DRD4, the gene encoding the dopamine D4 receptor, has also attracted interest as a candidate gene.…”