Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder

Abstract

Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral problem afflicting 5-10% of children and adolescents and persisting into adulthood in 30-50% or more of cases.1,2 Family, twin, and adoption studies suggest genetic factors contribute to ADHD and symptoms of inattention, impulsivity, and hyperactivity.3-5 Because stimulant intervention is effective in reducing ADHD symptoms in about 70-80% of cases, molecular genetic investigations of genes involved in dopamine regulation are currently underway by many groups.6-8 In a case control study of the dopamine D4 receptor gene (DRD4) and ADHD, La Hoste and colleagues 9 found an increase of a 7-repeat variant of a 48-bp VNTR in exon 3 10 among ADHD subjects compared to controls. Swanson and colleagues 11 replicated this finding in a sample of 52 ADHD probands and their biological parents using a haplotype relative risk analysis. Here, we describe linkage investigations of the VNTR and ADHD in affected sibling pair (ASP) families and singleton families using both the transmission disequilibrium test (TDT)12 and a mean test of identity-bydescent (IBD) sharing. Using the TDT in the total sample, the 7 allele is differentially transmitted to ADHD children (P = 0.03) while the mean test revealed no evidence of increased IBD sharing among ASPs. In the current sample, the 7 allele attributes a 1.5-fold risk for developing ADHD over non-carriers of the allele estimated under a model described by Risch and Merikangas.13

Dopamine D4 Receptor Gene Novelty or Nonsense?

“…Approaches using transmission disequilibrium, whereby the frequency of transmissions of each allele from parents with two distinct alleles to their children is compared to nontransmission of that allele, have been shown to be insensitive to population stratification (Spielman and Ewens 1996). This approach has been used for DRD4 in Tourette's syndrome (Grice et al 1996;Hebebrand et al 1997) with contradictory results, as well as for ADHD (Swanson et al 1998;Smalley et al 1998). Missing parental DNA may make such an approach unfeasible in certain circumstances, and one alternative utilizes siblings as controls (Curtis, 1997).…”

“…However, a statistic that considers all alleles together (Schaid 1996) does not reach conventional significance (p ϭ .074). Two recent studies of the DRD4 VNTR is ADHD provide weak positive results (Rowe et al 1998;Smalley et al 1998); whereas, another is negative (Castellanos et al 1998).…”

“…We have made a number of suggestions to improve the reporting and interpretation of such studies, including the use of correction for multiple statistical comparisons, the use of linkage disequilibrium studies, and performing haplotype analysis. Case (n ϭ 39) matched-control (n ϭ 39) study of ADHD DSM-IV 7 allele frequency 22% in patients vs. 9% in controls Swanson et al 1998 ADHD proband-parent trios (n ϭ 52) DSM-IV Allele-wise transmission disequilibrium for the 7 allele ( 2 ϭ 4.65, 1 df, p Ͻ .035) Rowe et al 1998 Cases (n ϭ 70 combined type; n ϭ 38 inattentive type), controls (n ϭ 71) Emory Diagnostic Rating Scale, for DSM-IV Presence of 7 allele higher in combined type ( 2 ϭ 5.9, 1 df p Ͻ .01) and inattentive type ( 2 ϭ 4.6, 1 df p Ͻ .05) Smalley et al 1998 133 families with ADHD probands DSM-IIIR or DSM-IV Transmission disequilibrium of 7 allele ( 2 ϭ 5.24, 1 df p р .02) Castellanos et al 1998 Cases (n ϭ 41) and controls (56) DSM-IIIR Allelic and genotypic frequencies compared between cases and controls, ns…”

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).…”

Dopaminergic System Genes in ADHD Toward a Biological Hypothesis

“…Furthermore, the 7 repeat allele of DRD4 mediates a blunted response to dopamine (Ashgari et al 1995). To date, there have been 16 studies examining for association between the 7 repeat DRD4 polymorphism and ADHD, with positive results in many (LaHoste et al 1996;Swanson et al 1998b;Smalley et al 1998;Rowe et al 1998;Faraone et al 1999;Muglia et al 2000;Holmes et al 2000;Sunohara et al 2000;Tahir et al 2000a;Mill et al 2001), but not all (Castellanos et al 1998; Comings et al 1999;Eisenberg et al 2000;Hawi et al 2000a;Kotler et al 2000;Todd et al 2001) studies. A recent meta-analysis of DRD4 by Faraone et al 2001 supported an overall association (albeit small) between DRD4 and ADHD.…”