Attention-deficit hyperactivity disorder and the gene for the dopamine D5 receptor

Abstract

A recent study has suggested a possible association of a polymorphism near the dopamine D5 receptor gene (DRD5) and attention-deficit hyperactivity disorder. 1 The polymorphism studied was a (CA)n repeat located in the cosmid containing the D5 receptor gene 2 and the allele that was reported to be associated with attention-deficit hyperactivity disorder (ADHD) was the 148-bp allele. In this study we sought to replicate this finding by testing for biased transmission of the alleles at this same polymorphism in a sample of 92 families with an ADHD proband. We did not observe significant evidence for biased transmission of the 148-bp allele, however we did observe biased transmission of two other alleles, the 136-bp allele and the 146-bp allele. For these two alleles the bias was for these two alleles not to be transmitted to the ADHD children. The number of informative transmissions for these two alleles was small, therefore it would be premature to make any conclusions from our study concerning the role of DRD5 in ADHD. Molecular Psychiatry (2000) 5, 548-551.The dopamine receptor D5, located on chromosome 4p15.1-p15.3, 3 is a member of the guanine nucleotidebinding (G-protein) receptors family and is close in structure to the D1 receptor. 4,5 Both the D1 and D5 receptors stimulate adenyl cyclase activity via G-protein coupling however the D5 receptors have a 10-fold higher affinity for dopamine than do the D1 receptors. 4,5 An association with an allele at the dopamine D5 receptor locus (DRD5) and ADHD has been reported using a sample of 91 nuclear families (69 trios and 22 parent-proband pairs) using the haplotype relative risk analysis and the transmission disequilibrium test.

Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5

“…The previously reported 'protective' 146-bp allele 15 was under-represented among transmitted alleles (P ¼ 0.02), while a trend emerged for increased transmission of the DRD5.148 allele (P ¼ 0.053), also consistent with prior reports. 16 Another putative risk allele reported by Barr et al, 15 the DRD5.136, showed no significant biased transmission (P ¼ 0.178), but the small number of informative meioses (N ¼ 27) makes extrapolation from either our study or that of Barr et al, 15 difficult. Previous findings of association prompted the analysis of the association of these particular alleles with ADHD susceptibility.…”

“…15,16,18,42,45 While Daly et al found that a 148-bp allele was preferentially transmitted to affected offspring, Barr did not identify this excess of transmission, but rather found that two minor alleles of this same polymorphism displayed a preferential lack of transmission to affected offspring. We examined the same polymorphism and found a trend consistent with Daly et al's finding of increased transmission of the 148-bp allele and a significant lack of transmission of the 146-bp to affected offspring.…”

“…Polymorphisms in DRD4, DAT1, DRD2 and DRD5 have been widely studied. [12][13][14][15][16][17][18] While positive and negative findings exist, viable reasons for betweenstudy inconsistencies include insufficient power to detect the involvement of genes of small effect, genetic and etiologic heterogeneity of ADHD, and different study designs and sample characteristics.…”

The dopamine transporter gene is associated with attention deficit hyperactivity disorder in a Taiwanese sample

“…In particular, replicated associations have been reported with the dopamine D4 and D5 receptors (DRD4 and DRD5), 4,[11][12][13] the dopamine transporter (DAT1) and the serotonin 1B receptor (5HT1B) 14,15 genes. Although the identification of such consistent findings is unusual in the study of human behavioural disorders, uncertainties remain over their validity and further evidence is required before we can be confident that the reported findings represent true genetic associations.…”

Attention-deficit hyperactivity disorder and the adrenergic receptors α1C and α2C

“…[15][16][17][18] Information for the diagnosis of ADHD and comorbid conditions was gathered through a semi-structured interview for parents (Parent Interview for Child Symptoms, PICS-IV; Schachar and Ickowicz, unpublished) and teachers (Teacher Telephone Interview-IV, TTI; Tannock and Schachar, unpublished). This information was supplemented with the following questionnaires and child assessments: Conners Parent and Teacher Rating Scales-Revised, 19 the Ontario Child Health Survey Scales-Revised, 20 Wide Range Achievement Test-III, 21 Clinical Evaluation of Language Fundamentals 3rd Edition, 22 Children's Depression Inventory, 23 and Children's Manifest Anxiety Scale.…”