The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity disorder

Abstract

Keywords: DRD2; dopamine receptor 2; attention deficit hyperactivity disorder (ADHD)The relationship of the DRD2 TaqI-A1 allele to hyperactive/impulsive and inattentive symptoms of attention deficit hyperactivity disorder (ADHD) in children and adolescents was examined in a sample of clinic-referred children and their siblings, and control children and their siblings (n = 236). The contribution of genetic dominance and additivity to mean differences among the A2A2, A1A2, and A1A1 genotypes was estimated using structural equation modeling. The effect of genetic additivity was statistically significant for both traits in an analysis of all children. The heritability from the DRD2 locus was estimated at 4.27% for hyperactiveimpulsive symptoms and 2.12% for inattentive symptoms. Children with the A2A2 genotype had the highest mean level of symptoms. To control for any possible effects of population stratification, this analysis was repeated with parental genotypes as controls. In this smaller sample, although the direction of the effect was the same as that in the whole sample, the genotypic differences failed to reach conventional significance levels and the effect sizes were smaller (h 2 = 1.62% and 0.79%, respectively). Furthermore, a genotype relative risk test of children who had questionnaire-based diagnoses of ADHD also failed to yield evidence of either association or linkage. Given that the A1 allele was expected to be the high risk allele, and that results were non-significant in tests that controlled for population heterogeneity, we doubt that this DRD2 polymorphism influences symptoms of ADHD in childhood.The dopamine receptor 2 gene (DRD2) has been the focus of considerable research linking genetic polymorphisms with behavioral traits. The most frequently studied mutation in DRD2 is a TaqI restriction site in the 3Ј untranslated region of the gene. 1 It does not alter the amino acid sequence of the DRD2 protein, and its functional significance, if any, is unknown. This study examines the relation of the TaqI polymorphism to symptoms of hyperactivity-impulsivity and inattention, the symptom dimensions that underlie DSM-IV diagnoses of attention deficit hyperactivity disorder (ADHD).There is reason to expect genes in dopaminergic brain pathways to be related to childhood ADHD. The dopaminergic pathway mediates responsiveness to reward and is implicated in the rewarding action of abused drugs such as cocaine and alcohol. 2,3 Further evidence for the importance of the dopaminergic pathway to ADHD comes from a knockout-gene study in mice. 4 In this study, mice that were homozygous for deactivation of the dopamine transporter gene (DAT1) were five to six times more active and had dopamine remain active in the synaptic cleft 100 times longer than heterozygous and wild-type mice. In our previous work, we found association and linkage between ADHD and a polymorphism in DAT1 and association between ADHD and another polymorphism in the dopamine receptor D4 gene (DRD4). 5,6 There was also some evidence for heteroge...

Dopaminergic System Genes in ADHD Toward a Biological Hypothesis

“…Comings et al (1991) found the A1 allele of the Taq I polymorphism of the D2 receptor gene to be more prevalent in patients with ADHD, compared with controls. Work by Rowe et al (1999), however, did not show linkage or association between DRD2 and ADHD. Barr et al (2000b) found no association between two DRD3 polymorphisms (located at exon I and intron 5) and ADHD.…”

Association between the dopamine D2 receptor TaqI A2 allele and low activity COMT allele with obsessive–compulsive disorder in males

“…Since other reports of associations between the A2 allele and similar neuropsychiatric disorders are scarce, the association of the A2 allele in our sample is difficult to interpret. The A2 allele has previously been related to hyperactive and impulsive symptoms in attention deficit hyperactivity disorder (ADHD) in a sample of 166 children and to compulsive smoking habits in 793 subjects (Rowe et al, 1999;Hamajima et al, 2002). Interestingly, the ADHD sample comprised 81% males, and the association with compulsive smoking was only significant for males.…”

An examination of the behavioral and neuropsychological correlates of three ADHD candidate gene polymorphisms (DRD4 7+, DBH TaqI A2, and DAT1 40 bp VNTR) in hyperactive and normal children followed to adulthood

“…The greatest research has been on DRD4 with 7 repeats and the DAT1 40bp VNTR (Comings et al 1991, Cook et al 1995, Comings et al 1996, LaHoste et al 1996, Gill et al 1997, Swanson et al 1997, Castellanos et al 1998, Smalley et al 1998, Swanson et al 1998, Daly et al 1999, Farone et al 1999, Rowe et al 1999, Comings et al 2000, Eisenberg et al 2000, Kotler et al 2000, Muglia et al 2000, Tahir et al 2000 . Cook et al (1995) was among the first to find preferential transmission of the 40bp allele (allele 3) of a VNTR in the 3′ UTR of the DAT1 40bp VNTR gene (12p12.3), a finding replicated by others, but not all investigators (Gill et al 1997, Daly et al 1999).…”