No abstract

Several studies have implicated the dopamine transporter gene (DAT1) as conferring susceptibility to attention deficit hyperactivity disorder (ADHD), in particular, a VNTR situated at the 3' end of the gene. In addition, the 10-repeat VNTR allele associated with ADHD has been reported to be associated with an over-active transporter protein (DAT). Thus children possessing this variant might be particularly responsive to methylphenidate, a drug known to act by blocking DAT. We have examined this hypothesis and now report an association between the 10-repeat VNTR DAT1 polymorphism and retrospectively rated methylphenidate response in a sample of 119 Irish children with ADHD (chi(2) = 7.918, df = 1, P = 0.005). Our findings suggest a role for the 10-repeat DAT1 risk allele in medication response and may help to predict positive clinical outcome in ADHD.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable and heterogeneous disorder, which usually becomes apparent during the first few years of childhood. Imbalance in dopamine neurotransmission has been suggested as a factor predisposing to ADHD. However, evidence has suggested an interaction between dopamine and serotonin systems in the pathophysiology of the disorder. Studies using selective agonists of the different 5-HT receptors microinjected into selected brain structures have shown a positive modulating effect on the functional activities of the mesotelencephalic dopaminergic system. This suggests that some of the genetic predisposition to ADHD might be due to DNA variation at serotonin system genes. In this study, we investigated polymorphisms in HTR 1B and HTR 2A (which encode the serotonin receptors 5-HT 1B and 5-HT 2A respectively) in a European ADHD sample. Using haplotype based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) analyses, we observed significant preferential transmission of the allele 861G of the HTR 1B in the total sample (for HHRR; 2 = 7.4, P = 0.0065 and TDT; ( 2 = 6.4, P = 0.014). Analysis of HTR 2A failed to reveal evidence of association or linkage between the His452Tyr polymorphism and ADHD in the total sample. However, a significantly increased transmission of the allele 452His was observed in the Irish sample alone ( 2 = 4.9, P = 0.026). These preliminary data suggest an important role for the serotonin system in the development of ADHD. Further studies, preferentially including different ethnic groups are required to substantiate these findings.

Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric condition characterized by hyperactive-impulsive behaviour and persistent inattention. Individuals with this condition experience social and academic dysfunction. Although the aetiology of ADHD is not known, it is postulated that a developmental failure in the brain mechanism that underlies self-control and inhibition is involved.2 ADHD affects approximately 3-6% of children and adolescents from different geographical regions worldwide.3 Boys are affected more frequently than girls, with the ratio ranging from 3:1 to 9:1. 4 Family, twin and adoption studies have indicated a strong genetic component in susceptibility to ADHD. An approximate five-to six-fold increase in the frequency of ADHD among first-degree relatives when compared with the general population was reported.5 A probandwise concordance rate of 72% monozygotic twins and 32% same-sex dizygotic twins was observed. 6 A number of twin studies have estimated the heritability of ADHD to range from 39% to 91% for various symptoms of the disorder. 7,8 Adoption studies have also supported a genetics component for ADHD. In a recent study Sprich et al 9 reported 6% of the adoptive parents of adopted ADHD probands had ADHD compared with 18% of the biological parents of non-adopted ADHD probands and 3% of the biological parents of the control.The dopaminergic neurotransmission systems have been implicated in the pathology of ADHD. Genes of the dopamine system have been linked with ADHD for a number of reasons including: (1) the reduction in symptoms brought about by pharmacological agents (such as methylphenidate) that primarily act in the dopaminergic system; 10 (2) the results from recent imaging studies of an ADHD brain implicate brain structures with rich dopamine content, such as the fronto-striatal circuitary in the aetiology of ADHD; 3 (3) animal model studies such as the mouse model lacking dopamine transporter (ie DAT1 knockout mice) demonstrate a link between the dopamine system and ADHD. Mice lacking DAT1 have high extracellular striatal dopamine levels and display increased locomotor activity, a typical characteristic of the ADHD phenotype. 11 Recently, several association studies utilizing DNA variants at DAT1, DRD4, DRD5 and DBH have suggested the involvement of these loci as susceptibility variants (genes of minor effect) for ADHD.

Converging evidence has implicated abnormalities of dopamine neurotransmission to the pathology of attention deficit hyperactivity disorder (ADHD).Attention Deficit Hyperactivity Disorder (ADHD) is a common condition of childhood affecting 3-6% of school age children worldwide (Barkley 1990), with males being affected three times more than females (Anderson et al. 1987; Baumgartel et al. 1995). Its core clinical features include excessive motor activity, impaired attention, and impulsivity. ADHD causes marked educational, social, and family difficulties for sufferers and their relatives. The condition is of early onset (usually before age 7) and tends to persist throughout childhood. Moreover, approximately 30-60% of children with ADHD have persisting psychopathology in adulthood (Gittelman et al. 1985;Weiss and Hechtman 1986; Barkley 1990;Swanson et al. 1998a). The exact etiology of ADHD is Received March 8, 2001; revised February 12, 2002; accepted February 20, 2002. Online publication: 2/28/02 at www.acnp.org/citations/ Npp022802254. 608 A. Kirley et al. N EUROPSYCHOPHARMACOLOGY 2002 -VOL . 27 , NO . 4 unknown, but a substantial genetic element exists. This has been demonstrated by family (Biederman et al. 1990(Biederman et al. , 1992Faraone et al., 1992Faraone et al., , 1994, twin (Thapar et al. 1995;Silberg et al. 1996;Levy et al. 1997), and adoption studies (Alberts-Corush et al. 1986; Cadoret and Stewart 1991). The heritability (h 2 ) of ADHD has been estimated to be .50-.98 (Gjone et al. 1996;Levy et al. 1997). The exact mode of transmission remains unknown. Segregation analyses (Morrison and Steward 1974;Deutsch et al. 1990, Faraone et al. 1992, Hess et al. 1995 have proposed models of inheritance from major gene effects through oligogenic to polygenic and multifactorial models, but the differences in statistical "fit" between multifactorial genetic models and single gene inheritance is modest. The multifactorial concept is consistent with ADHD's high population prevalence (2-7%), high concordance in monozygotic twins (68-81%), but modest recurrence risks to first-degree relatives.Dysregulation in catecholamine neurotransmission is implicated in the pathophysiology of ADHD (Faraone and Biederman 2002). The dopaminergic neurotransmitter system has been most extensively studied. This article will focus mainly on its role in the etiology of ADHD. Evidence to support dopaminergic dysfunction in ADHD derives from three research areas: the neuropharmacology of stimulant medication (Zametkin and Rapoport 1987; Amara and Kuhar 1993), the behavior and biochemistry of animal models (Giros et al. 1996;Gainetdinov et al. 1999, Russell 2000, and neuroimaging studies in ADHD adults (Dougherty et al. 1999, Krause et al. 2000, and Faraone and Biederman 2002. For this reason, many molecular genetic studies have focused on dopamine system genes.The gene encoding the dopamine transporter, DAT1, was the initial candidate gene studied. This gene is of particular interest, as the transporter is the principal target...