DAT1, DRD4, and DRD5 polymorphisms are not associated with ADHD in Dutch families

Bakker, Steven C.; Meulen, Emma M. van der; Oteman, Nicole; Schelleman, Hedi; Pearson, P. L.; Buitelaar, Jan K.; Sinke, Richard J.

doi:10.1002/ajmg.b.30089

Cited by 57 publications

(32 citation statements)

References 20 publications

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“…Many association studies between DRD4 and ADHD have been performed, although results are often controversial. 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].…”

Section: Discussionsupporting

confidence: 93%

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

Sánchez-Mora

Ribasés

Casas

et al. 2011

American J of Med Genetics Pt B

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Attention-deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting about 4-8% of children. ADHD persists into adulthood in around 65% of cases, either as the full condition or in partial remission with persistence of symptoms. Pharmacological, animal and molecular genetic studies support a role for genes of the dopaminergic system in ADHD due to its essential role in motor control, cognition, emotion, and reward. Based on these data, we analyzed two functional polymorphisms within the DRD4 gene (120 bp duplication in the promoter and 48 bp VNTR in exon 3) in a clinical sample of 1,608 adult ADHD patients and 2,352 controls of Caucasian origin from four European countries that had been recruited in the context of the International Multicentre persistent ADHD CollaboraTion (IMpACT). Single-marker analysis of the two polymorphisms did not reveal association with ADHD. In contrast, multiplemarker meta-analysis showed a nominal association (P ¼ 0.02) of the L-4R haplotype (dup120bp-48bpVNTR) with adulthood ADHD, especially with the combined clinical subtype. Since we previously described association between adulthood ADHD and the dopamine transporter SLC6A3 9R-6R haplotype (3 0 UTR VNTR-intron 8 VNTR) in the same dataset, we further tested for gene Â gene interaction between DRD4 and SLC6A3. However, we detected no epistatic effects but our results rather suggest additive effects of the DRD4 risk haplotype and the SLC6A3 gene.

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Section: Discussionsupporting

confidence: 93%

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

Sánchez-Mora

Ribasés

Casas

et al. 2011

American J of Med Genetics Pt B

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“…The application of foregoing criteria yielded 30 studies [Cook et al, 1995;Gill et al, 1997;Waldman et al, 1998;Daly et al, 1999;Jiang et al, 1999;Palmer et al, 1999, in Chinese;Holmes et al, 2000;Lunetta et al, 2000;Swanson et al, 2000;Barr et al, 2001;Curran et al, 2001;Roman et al, 2001;Todd et al, 2001;Kirley et al, 2002;CEDAR from Maher et al, 2002;Muglia et al, 2002;Chen et al, 2003;Qian et al, 2003, in Chinese;Hawi et al, 2003;Kustanovich et al, 2004;Qian et al, 2004;Bakker et al, 2005;Bobb et al, 2005;Feng et al, 2005;Langley et al, 2005; Brookes et al [2006] involved two samples so they were included as two independent studies, respectively. Table II gives the odds ratios and their 95% CIs for the 18 TDT studies.…”

Section: Resultsmentioning

confidence: 99%

A meta‐analysis of association studies between the 10‐repeat allele of a VNTR polymorphism in the 3′‐UTR of dopamine transporter gene and attention deficit hyperactivity disorder

Yang

Chan

Jin

et al. 2007

American J of Med Genetics Pt B

163

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The association between the 10-repeat allele of the dopamine transporter gene (DAT) and attention deficit hyperactivity disorder (ADHD) is uncertain. This study aimed to conduct a meta-analysis of the association between the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region (UTR) of the DAT1 gene and ADHD. We pooled up 18 published transmission disequilibrium test (TDT) studies between the 40-base pair VNTR polymorphism in the3'-UTR of the DAT1 gene and ADHD. It included a total of 1,373 informative meioses, 7 haplotype-based haplotype relative risk (HHRR) studies, and 6 case-control-based association studies. There were statistically significant evidences for heterogeneity of the odds ratio in TDT and HHRR studies (P < 0.10), but not in case-control studies. The results of random effects model showed small but significant association between ADHD and the DAT1 gene in TDT studies (OR = 1.17, 95% CI = 1.05-1.30, chi-square = 8.11, df = 1, P = 0.004), but not in HHRR and case-control studies. The 10-repeat allele of a VNTR polymorphism in the 3'-UTR the DAT1 gene has a small but significant role in the genetic susceptibility of ADHD. These meta-analysis findings support the involvement of the dopamine system genes in ADHD liability variation. However, more work is required to further identify the functional allelic variants/mutations that are responsible for this association.

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“…This association has been supported by others, 32,33 but not all studies. [34][35][36] Two meta-analyses showed no significant association (P = 0.21 and P = 0.20) of the 3 0 VNTR with ADHD. 37,38 Importantly, the 5 0 and 3 0 regions of the DAT1 locus are separated by a recombinational 'hot spot' between exons 7 and 9.…”

Section: Introductionmentioning

confidence: 92%

Association and linkage of allelic variants of the dopamine transporter gene in ADHD

et al. 2007

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Previously, we had reported a genome-wide scan for attention-deficit/hyperactivity disorder (ADHD) in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 (parametric HLOD analysis under a dominant model) near the dopamine transporter gene (DAT1). We genotyped 30 single nucleotide polymorphisms (SNPs) in this candidate gene and its 5 0 region in 329 families (including the 102 initial families) with 523 affected offspring. We found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P = 0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n = 3) tested blocks (P = 0.0048); (3) within block two we detected a nominal P = 0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, our linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains our linkage peak and that rs463379 (P < 0.05) is the only SNP of the above haplotype that contributed to the linkage signal. In sum, we have accumulated evidence that genetic variation at the DAT1 locus underlies our ADHD linkage peak on chromosome 5; additionally solid association for a single SNP and a haplotype were shown. Future studies are required to assess if variation at this locus also explains other positive linkage results obtained for chromosome 5p.

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DAT1, DRD4, and DRD5 polymorphisms are not associated with ADHD in Dutch families

Cited by 57 publications

References 20 publications

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

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

A meta‐analysis of association studies between the 10‐repeat allele of a VNTR polymorphism in the 3′‐UTR of dopamine transporter gene and attention deficit hyperactivity disorder

Association and linkage of allelic variants of the dopamine transporter gene in ADHD

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