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

Abstract

The purpose of this meta-analysis was to examine whether association studies between attention deficit/hyperactivity disorder (AD/HD) and the dopamine receptor 4 gene 7-repeat (DRD4 7R) allele vary systematically based on study characteristics. A total of 27 empirical studies with 28 distinct samples using either case-control or family-based association analyses were included. Consistent with previous meta-analytic work [Gizer et al. (2009), Hum Genet 126:51-90], the DRD4 7R allele was associated with AD/HD across studies (OR = 1.33; 95% CI = 1.16-1.53, z = 4.04, P = 0.00005) and there was significant systematic variability among studies (Q = 54.24; P = 0.001; I(2) = 50.22). To account for the variability among studies, sample and study level covariates were examined. No differences in overall effect size emerged between family-based and case-control studies. However, the risk allele frequency in the control population accounted for a significant portion of the variance in overall effect size within case-control studies. In addition, evidence for the association between the DRD4 7R allele and distinct AD/HD subtypes emerged across family-based and case-control studies. The proportion of AD/HD, combined type individuals within the AD/HD sample was associated with a significant increase in the magnitude of association between the DRD4 7R allele and AD/HD. Conversely, an increase in the proportion of AD/HD, predominantly inattentive type individuals within the AD/HD sample was associated with a decrease in study effect size. Implications regarding AD/HD etiological and phenotypic heterogeneity are discussed.

Exploring DRD4 and its interaction with SLC6A3 as possible risk factors for adult ADHD: A meta‐analysis in four European populations

“…Our results are in agreement with previous studies supporting the validity of the different DSM-IV subtypes, mainly the combined subtype, and suggesting the participation of differential genetic factors in distinct ADHD clinical groups [Rasmussen et al, 2004;Larsson et al, 2006;Sobanski et al, 2008;Ribases et al, 2009]. Interestingly, Smith [2010] performed a meta-analysis of 28 association studies between ADHD and the 48bpVNTR in DRD4 and observed that increases in the proportion of combined ADHD patients within an ADHD sample were associated with an increase in the magnitude of the effect. These results are consistent with the hypothesis that DRD4 is more strongly associated with combined ADHD than with inattentive ADHD and are in line with the hypothesis that hypofunctioning in mesocortical and mesolimbic dopaminergic pathways better characterize the etiology of combined ADHD than inattentive ADHD [Sagvolden et al, 2005;Smith, 2010].…”

“…Interestingly, Smith [2010] performed a meta-analysis of 28 association studies between ADHD and the 48bpVNTR in DRD4 and observed that increases in the proportion of combined ADHD patients within an ADHD sample were associated with an increase in the magnitude of the effect. These results are consistent with the hypothesis that DRD4 is more strongly associated with combined ADHD than with inattentive ADHD and are in line with the hypothesis that hypofunctioning in mesocortical and mesolimbic dopaminergic pathways better characterize the etiology of combined ADHD than inattentive ADHD [Sagvolden et al, 2005;Smith, 2010]. This view is supported by the fact that variation in DAT1, another dopaminergic gene, is also more strongly associated with combined ADHD than with inattentive ADHD (e.g., Waldman et al, 1998).…”

“…On the other hand, Muglia et al [2000] suggested a role of the 7R allele in adult ADHD and, finally, although performed in childhood ADHD samples, several meta-analyses have demonstrated a significant association between this DRD4 allele and ADHD [Faraone et al, 2001;Faraone et al, 2005;Li et al, 2006;Gizer et al, 2009;Nikolaidis and Gray, 2010;Smith, 2010]. However, some of these meta-analyses detected significant heterogeneity in the effect size for DRD4 in the different studies [Li et al, 2006;Gizer et al, 2009;Smith, 2010]. Seaman et al [1999] subsequently identified a second common genetic variant in DRD4, the 120 bp duplication (dup120bp) located 1.2 kb upstream of the DRD4 translation initiation codon.…”

Serotonin transporter polymorphism moderates the effects of caregiver intrusiveness on ADHD symptoms among institutionalized preschoolers

“…Indeed, genes associated with monoamine neurotransmission have been implicated in its pathogenesis. Although significant research has focused on associations between inattention and hyperactivity symptom phenotypes and polymorphisms in genes such as dopamine receptors [15] or dopamine transporter [16], recent interest has been directed at the potential role of the serotonin transporter length polymorphism present in the promoter region of the gene that codes for the serotonin transporter (5-HTTLPR), at least in the case of home-reared children. This is one of two reasons why we focus on this polymorphism in the current inquiry.…”

Effects of Nicotine Deprivation and Replacement on BOLD-fMRI Response to Smoking Cues as a Function of DRD4 VNTR Genotype

“…Clearly, there is considerable ambiguity with regard to the role of DRD4 VNTR in nicotine dependence, and there is a need for larger, more systematic studies to clarify this relationship. Notably, a further complication is that the DRD4 7-repeat allele has most robustly been associated with attention deficit/hyperactivity disorder (ADHD) (Faraone, Doyle, Mick, & Biederman, 2001;Smith, 2010), which itself is linked to smoking (McClernon & Kollins, 2008), but most studies on the link between DRD4 VNTR and smoking do not integrate ADHD status or symptoms. In this study, individuals with a current ADHD diagnosis were excluded, but subclinical or undiagnosed individuals may have enrolled, a limitation that applies to virtually all studies in this area.…”