Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children

Abstract

Attention deficit hyperactivity disorder (ADHD) is a common disorder of childhood characterized by inattention, excessive motor activity, impulsivity, and distractibility. It is associated with serious disability in children, adolescents and adults. 1 The etiology of the disorder is unknown, but it has a strong genetic component. Pharmacological and biochemical studies have suggested that dopaminergic and noradrenergic systems are involved. 2 Using a sample of affected children and their parents we have found preferential transmission of alleles at polymorphisms at the dopamine transporter (DAT1), RR = 1.2 (1.05-1.37), P = 0.006, re-confirming and extending our previous findings for DAT1 3 (new sample one-tailed P = 0.039); dopamine-␤-hydroxylase (DBH), RR = 1.31 (1.09-1.56), P = 0.0027; and the dopamine D5 receptor (DRD5), RR = 1.67 (1.29-2.15), P = 0.00005. Transmission of the 'associated' alleles at DAT1 and DBH is stronger in familial cases, RR DAT1 = 1.29 (1.04-1.59), RR DBH = 1.49 (1.10-2.00), but for DRD5, transmission is stronger in non-familial cases, RR = 1.59 (1.05-2.42). TDT analysis of complete trios supports the HHRR analysis, with P Ͻ 0.05, for DAT1 P Ͻ 0.005 and DBH and P Ͻ 0.01 for DRD5. Attributable fractions for DAT1, DBH and DRD5 are calculated at 0.08, 0.12 and 0.20 respectively.ADHD affects between 4% and 6% of the school-age population. 4,5 It affects boys two to three times more frequently than girls and leads to significant behavioral problems, impaired family and social relationships and major difficulties in school. Many children with ADHD develop conduct disorder and the long-term outcome is poor. 1 ADHD is familial 6 and twin studies estimate heritability (h 2 ) at 80-90%. [7][8][9] The mode of transmission is unknown, but is likely to be due to many genes, each of small effect. Overall 1st.Deg.Rel is 5-6, 10 suggesting that relative risks at individual loci will be small, and below the resolution of linkage studies. 11 We 3 previously confirmed an association 12 with the 480-bp allele of a VNTR situated in the 3Ј untranslated region of the DAT1 gene. 13 A further replication of this finding is provided by Waldman et al. 14 However, recent work proposes a more complicated neurochemical process including relative hypo-and hyper-dopaminergic function and involving the noradrenergic system. 2 We therefore extended our studies to include other monoamine-related genes.The dopamine transporter gene is a member of a family of Na + and Cl − dependent neurotransmitter transporters containing twelve transmembrane domains. 15 This gene confers all of the pharmacological properties of the rat dopamine re-uptake carrier 16 including the capacity to bind cocaine and other psychostimulant drugs. A 40-bp polymorphic tandem repeat was identified in the 3Ј UTR and was used in the present study. Dopamine-␤-hydroxylase (D␤H) catalyses the conversion of dopamine to noradrenaline. The gene (DBH) is closely linked to the ABO blood group on chromosome 9q34. Enzyme activity in serum or plasma is a stable, hi...

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 (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.…”

“…Approximately 80% of the children in this study with ADHD also met diagnostic criteria for other disorders such as Oppositional Defiant Disorder and Conduct Disorder. Details of diagnosis and clinical criteria can be found in Daly et al (1999). Briefly, consensus diagnoses were made according to DSM-IV ADHD or UADD, either with or without comorbidity.…”

“…We (Daly et al 1999) reported association between the 148bp DRD5 allele and ADHD, using a family-based study design. Barr et al Less is known about the role of the remaining dopamine receptor genes as potential susceptibility loci.…”

“…Three groups refuted this finding (Barr et al 1999;Hawi et al 2000b;Tahir et al 2000b), and Eisenberg's group also failed to replicate the original finding . We (Daly et al 1999) reported association at the A2 allele of the Taq I polymorphism of the gene (DBH) encoding the Dopamine Beta Hydroxylase enzyme. Interestingly, Comings et al (1996) suggested that the DBH gene might have additive effects with DAT1 and DRD2 in a sample of Tourette syndrome patients with ADHD symptoms.…”

“…27, NO. 4 study is known to be in significant linkage disequilibrium (Daly et al 1999) with polymorphisms (in promoter and exon 2 regions) associated with reduced DBH enzyme activity (Cubells et al 1998). In experimental animals with decreased serum DBH, reduced conversion of dopamine to noradrenaline lessens negative feedback on tyrosine hydroxylase (Anden et al 1973; Axelrod and Weinshilboum 1972).…”