Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach

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).…”

“…Probands possessing at least one 7 allele had higher ratings of ADHD symptomatology, as compared to those without the 7 allele. This has recently been followed up with a study using a new sample of 52 probands with parental controls (Swanson et al 1998) employing the haplotype relative risk method, in which the alleles that the parents do not pass onto their children are used as the controls. The 7 allele was transmitted 30 times from the parents, as compared to 17 nontransmissions ( 2 ϭ 4.65, 1 df, p Ͻ .035).…”

“…The 7 allele was transmitted 30 times from the parents, as compared to 17 nontransmissions ( 2 ϭ 4.65, 1 df, p Ͻ .035). Results using linkage disequilibrium from the combined sample of 100 parent-ADHD proband trios reported elsewhere (Swanson et al 1998), and an unpublished proband and Adamson et al 1995 Finnish male alcoholics (n ϭ 113) and controls (n ϭ 113)…”

“…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…”

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.…”