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

Abstract

Polymorphisms of the dopamine receptor D4 gene DRD4, 11p15.5, have previously been associated with attention-deficit/hyperactivity disorder (ADHD) [Bobb et al., 2005; Am J Med Genet B Neuropsychiatr Genet 132:109-125;Faraone et al., 2005; Biol Psychiatry 57:1313-1323Thapar et al., 2005; Hum Mol Genet 14 Spec No. 2:R275-R282]. As a follow up to a pilot study [see Castellanos et al., 1998; Mol Psychiatry 3:431-434] consisting of 41 probands and 56 controls which found no significant association between the DRD4 7-repeat allele in exon 3 and ADHD, a greatly expanded study sample (cases n ¼ 166 and controls n ¼ 282) and long term follow-up (n ¼ 107, baseline mean age n ¼ 9, follow-up mean age of n ¼ 15) prompted reexamination of this gene. The DRD4 7-repeat allele was significantly more frequent in ADHD cases than controls (OR ¼ 1.2; P ¼ 0.028). Further, within the ADHD group, the 7-repeat allele was associated with better cognitive performance (measured by the WISC-III) (P ¼ 0.013-0.07) as well as a trend for association with better long-term outcome. This provides further evidence of the role of the DRD4 7-repeat allele in the etiology of ADHD and suggests that this allele may be associated with a more benign form of the disorder. INTRODUCTIONAttention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable childhood disorder defined by chronic inattention, hyperactivity, and impulsivity based on criteria specified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) [American Psychiatric Association, 1994]. 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. Despite a few inconsistencies in reported associations of this VNTR and ADHD [Eisenberg et al., 2000;Hawi et al., 2000;Sunohara et al., 2000;Marino et al., 2003;Purper-Ouakil et al., 2005] the majority of reports and several meta-analyses have found positive support for the association [LaHoste et al., 1996;Smalley et al., 1998;Comings et al., 1999;Curran et al., 2001;Mill et al., 2001;Roman et al., 2001;Holmes et al., 2002;Bobb et al., 2005;Faraone et al., 2005;Bhaduri et al., 2006].In the present study, we used both case-control and familybased designs to test the association between ADHD and the DRD4 7-repeat allele using an expanded sample from a previous pilot study [Castellanos et al., 1998] of ADHD patients recruited as part of a d...

Meta‐analysis of the heterogeneity in association of DRD4 7‐repeat allele and AD/HD: Stronger association with AD/HD combined type

“…One study was excluded because the control sample did not consist of healthy individuals [Ballon et al, 2007]. Note that a number of included case-control studies reported family-based association ORs [Hawi et al, 2000;Holmes et al, 2000;Mill et al, 2001;Roman et al, 2001;Gornick et al, 2007]. In these studies, only the data from the case-control association analyses were reported as they were associated with more precise sample information, included more participants, and are comparable to family-based results [Evangelou et al, 2006].…”

A Haplotype of the Norepinephrine Transporter (Net) Gene Slc6a2 is Associated with Clinical Response to Atomoxetine in Attention-Deficit Hyperactivity Disorder (ADHD)

“…This familial aggregation is believed to be partially explained by genetic factors, as the heritability of ADHD has been reported to be between 75 and 91% (Faraone et al, 2005;Thapar et al, 2006;Masellis et al, 2006). Numerous vulnerability genes have been proposed in ADHD with some convergence for gene coding for the dopamine receptor D4 (Faraone et al, 2005;Gornick et al, 2007;Lasky-Su et al, 2007;Shaw et al, 2007) and the dopamine transporter (Faraone et al, 2005;Thapar et al, 2006;Masellis et al, 2006;Cook et al, 1995). The precise neurochemical pathophysiology of ADHD remains unknown.…”

Polymorphisms of the Dopamine D4 Receptor, Clinical Outcome, and Cortical Structure in Attention-Deficit/Hyperactivity Disorder

“…1 We recently also replicated this association, finding a significantly increased frequency of the 7-repeat allele in 169 children with ADHD (23%) compared with 265 healthy controls (17%). 2 Previous studies have suggested that carriers of the risk allele may also have a unique neuropsychological, [3][4][5][6] clinical, [7][8][9][10][11][12][13] and pharmacological 14 profile, although there remains considerable debate over the exact nature of this phenotype. The DRD4 7-repeat allele has also been linked with clinical outcome, albeit with divergent results.…”