Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD)

Abstract

Attention deficit hyperactivity disorder (ADHD) is

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

“…In this regard, although our data in the single-marker analysis are in agreement with previous reports showing no association between ADHD and the 48bpVNTR polymorphism [Roman et al, 2001;Todd et al, 2001;Bakker et al, 2005;Brookes et al, 2005;Carrasco et al, 2006;Johansson et al, 2008;Sonuga-Barke et al, 2008], they are contrary to others having reported on association between the 7R allele and the disorder Faraone et al, 2001;Maher et al, 2002;Wohl et al, 2005;Brookes et al, 2006;Li et al, 2006;Gizer et al, 2008Gizer et al, , 2009Biederman et al, 2009;Langley et al, 2009;Nikolaidis and Gray, 2010]. Likewise, our results for the DRD4 dup120bp polymorphism are in line with most of the literature, including a recent meta-analysis [Barr et al, 2001;Todd et al, 2001;Mill et al, 2003;Kirley et al, 2004;Brookes et al, 2005;Bhaduri et al, 2006;Gizer et al, 2009], but not with findings from the first two association analyses of this variation [McCracken et al, 2000].…”

“…In this regard, the 240 bp allele (long or L allele) showed enhanced binding capacity for the Sp1 transcription factor in a mobility shift assay and exhibited lower transcriptional activity than the 120 bp allele (short or S allele) in transfected cell lines [D'Souza et al, 2004;Ronai et al, 2004;Kereszturi et al, 2007]. Several studies have tested association between the DRD4 dup120bp polymorphism and ADHD but results are also controversial, showing no association [Barr et al, 2001;Todd et al, 2001;Brookes et al, 2005;Bhaduri et al, 2006;Gizer et al, 2009] or identifying either the L or S alleles as risk factors for ADHD [McCracken et al, 2000;Kustanovich et al, 2004;Kereszturi et al, 2007]. Accordingly, a recent meta-analysis performed by Gizer et al [2009] found no association between childhood ADHD and either allele.…”

The dopamine D4 receptor and the hyperactivity phenotype: a developmental-epidemiological study

“…Twelve published studies have shown association or association and linkage between the 7-repeat allele of DRD4 and ADHD, [12][13][14][15][16][17][18][19][20][21][22][23] whereas seven have found no association. [24][25][26][27][28][29][30] A recent meta-analysis of published and unpublished data calculated an odds ratio (OR) of 1.9 (95% CI: 1.4-2.2, P = 0.00000008) from seven case-control studies and 1.4 (95% CI: 1.1-1.6, P = 0.02) from 14 family-based studies. 31 Difficulties in replicating QTL findings in psychiatry have prompted a call for well-characterised samples with a wealth of phenotypic data.…”

Functional polymorphisms in dopamine and serotonin pathway genes

“…There are consensus-binding sequences for several transcription factors within the duplication, suggesting that this polymorphism may have a role in regulating transcriptional activity. Interestingly, a report showed a strong association of this tandem duplication with children having ADHD with the inattentive phenotypic subtype (P 5 0.005), and hypothesized that the duplication could be a risk factor by decreasing expression of the DRD4 gene [McCracken et al, 2000]. Other evidence supporting an association of this polymorphism together with a haplotype of markers in the 5 0 end of the gene and ADHD has been reported (P 5 0.03) .…”