A family-based and case-control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder

Abstract

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition of early childhood onset characterised by marked inattention, hyperactivity and impulsiveness. Molecular genetic investigations of ADHD have found positive associations with the 480-bp allele of a VNTR situated in the 3Ј untranslated region of DAT1 and allele 7 of a VNTR in exon 3 of DRD4. A number of independent studies have attempted to replicate these findings but the results have been inconsistent. We used both family-based and case control approaches to examine these polymorphisms in a sample of 137 children diagnosed with ICD-10, DSM-IV or DSM-III-R ADHD. We found no evidence of association with the DAT1 polymorphism, despite a sample size that has up to 80% power to detect a previously reported effect size. We observed a significant increase in the DRD4 7 repeat allele amongst ADHD probands (21.7%) and their parents (18.9% in mothers, 22.3% in fathers), compared to ethnically matched controls (12.8%). However TDT analysis showed no preferential transmission of allele 7 to ADHD probands. Molecular Psychiatry (2000) 5, 523-530.

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.…”

“…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.…”

Polymorphisms in the 3′-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression

“…[22][23][24] The discovery of a variable number of tandem repeat sequences (VNTR) in the 3Ј-UTR of the DAT gene 25 broadened the scope of potential sources of DAT diversity. [26][27][28] Research to link the number of tandem repeat units in the VNTR (ie, the length of the 3Ј-UTR) with dopamine-related disorders uncovered an association between alleles with the 10-repeat length and ADHD [29][30][31][32][33] (but see Holmes et al 34 ). Less consistently, alleles with the 9-repeat length have been associated with cocaine-induced paranoia and alcohol or nicotine addictions.…”

Association of the dopamine receptor D4 (DRD4) gene 7‐repeat allele with children with attention‐deficit/hyperactivity disorder (ADHD): An update

“…Family, twin and adoption studies, as well as linkage and association studies, have shown strong genetic contributions to the etiology of ADHD [Faraone and Biederman, 1998;Fisher et al, 2002;Ogdie et al, 2003; ArcosBurgos et al, 2004]. The most consistently replicated candidate gene in ADHD genetics is the association with the dopamine receptor D4 gene (DRD4) [LaHoste et al, 1996;Smalley et al, 1998;Swanson et al, 1998;Comings et al, 1999;Faraone et al, 1999;Holmes et al, 2000;Muglia et al, 2000;Tahir et al, 2000;Curran et al, 2001;Mill et al, 2001;Roman et al, 2001;Bhaduri et al, 2006]. The majority of these studies have reported on a variable number tandem repeat (VNTR) polymorphism in exon 3 of the DRD4 gene.…”