Association and Linkage of the Dopamine Transporter Gene and Attention-Deficit Hyperactivity Disorder in Children: Heterogeneity owing to Diagnostic Subtype and Severity

Abstract

Attention-deficit hyperactivity disorder (ADHD) affects approximately 3%-5% of children in the United States. In the current psychiatric nomenclature, ADHD comprises three subtypes: inattentive, hyperactive-impulsive, and combined. In this study, we used four analytic strategies to examine the association and linkage of the dopamine transporter gene (DAT1) and ADHD. Our sample included 122 children referred to psychiatric clinics for behavioral and learning problems that included but were not limited to ADHD, as well as their parents and siblings. Within-family analyses of linkage disequilibrium, using the transmission disequilibrium test (TDT), confirmed the 480-bp allele as the high-risk allele. In between-family association analyses, levels of hyperactive-impulsive symptoms but not inattentive symptoms were related to the number of DAT1 high-risk alleles. Siblings discordant for the number of DAT1 high-risk alleles differed markedly in their levels of both hyperactive-impulsive and inattentive symptoms, such that the sibling with the higher number of high-risk alleles had much higher symptom levels. Within-family analyses of linkage disequilibrium, using the TDT, suggested association and linkage of ADHD with DAT1 and that this relation was especially strong with the combined but not the inattentive subtype. The relation of DAT1 to ADHD increased monotonically, from low to medium to high levels of symptom severity. Our results replicate and extend previous findings of the association between the DAT1 gene and childhood ADHD. This represents one of the first replicated relations of a candidate gene and a psychiatric disorder in children.

Association and linkage of allelic variants of the dopamine transporter gene in ADHD

“…Cook et al 31 first reported an association of the 10-repeat allele with ADHD. This association has been supported by others, 32,33 but not all studies. [34][35][36] Two meta-analyses showed no significant association (P = 0.21 and P = 0.20) of the 3 0 VNTR with ADHD.…”

Exploring DRD4 and its interaction with SLC6A3 as possible risk factors for adult ADHD: A meta‐analysis in four European populations

“…These results are consistent with the hypothesis that DRD4 is more strongly associated with combined ADHD than with inattentive ADHD and are in line with the hypothesis that hypofunctioning in mesocortical and mesolimbic dopaminergic pathways better characterize the etiology of combined ADHD than inattentive ADHD [Sagvolden et al, 2005;Smith, 2010]. This view is supported by the fact that variation in DAT1, another dopaminergic gene, is also more strongly associated with combined ADHD than with inattentive ADHD (e.g., Waldman et al, 1998). Moroeover, it is possible that consideration of neuropsychological traits, comorbidities or personality data, not included in the present study, may help in the future to obtain better association signals with DRD4 than the analysis of the sole ADHD condition.…”

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.…”