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

Abstract

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.

Multicenter Analysis of the SLC6A3/DAT1 VNTR Haplotype in Persistent ADHD Suggests Differential Involvement of the Gene in Childhood and Persistent ADHD

“…Despite an impressive number of studies already performed, the role of DAT1 in ADHD, even in children, is still far from clear. The 3 0 -UTR VNTR has been investigated in multiple studies, but meta-analyses of the genotyping data are controversial (Maher et al, 2002;Faraone et al, 2005;Todd et al, 2005;Yang et al, 2007;Li et al, 2006). The same holds true for the current findings: although our metaanalysis included 1440 patients and 1854 controls, the p-values we report are only nominally significant (we did not carry out correction for multiple testing for the correlated tests).…”

“…Since the original publication in 1995 (Cook et al, 1995), many studies have investigated the association of this VNTR with ADHD, with variable results. Meta-analyses of the data have also not been consistent, with the most comprehensive ones showing little or no significant effect (Maher et al, 2002;Faraone et al, 2005;Todd et al, 2005;Yang et al, 2007;Li et al, 2006). Because of the number of positive reports and because of significant evidence of heterogeneity between data sets, systematic differences between data sets might explain the apparent discrepancies (Li et al, 2006).…”

Dopamine Transporter (SLC6A3) Genotype Impacts Neurophysiological Correlates of Cognitive Response Control in an Adult Sample of Patients with ADHD

“…However, findings are heterogeneous and may depend on the specific statistical analysis method (Todd et al, 2005;Li et al, 2006;Yang et al, 2007;Langley et al, 2005;Cheuk et al, 2006). Furthermore, in adult samples, the nine-repeat allele has been shown to be associated with the disease, suggesting a differential association depending on age, and a role of SLC6A3 in modulating the ADHD phenotype over life time (Franke et al, 2008(Franke et al, , 2010.…”

Candidate Gene Studies of Attention Deficit Hyperactivity Disorder

“…Bu durum mesokortikolimbik yolak ve nigrostriatal yolağın her ikisinde de aktivite azalmasına yol açabilir. [33] DAT ve DEHB arasındaki ilişkinin saptandığı ilk çalışma Cook ve arkadaşları tarafından yapılmış ve 480 bç'lik 10 tekrar alleli ve DEHB arasında anlamlı ilişki bulunmuştur. [34] Ardından yapılan çalışmaların bir kısmında 480 bç (10T) alleli ile ilişki bağımsız olarak tekrarlanmıştır.…”

“…[36] Bu çalışmalarda elde edilen farklı bulguların istatistiksel farklılıklar, örneklemlerin yanlılığı, yöntemsel farklılıklar ve DEHB'nin heterojenitesinden kaynaklanıyor olabileceği düşünülmüştür. [33] DAT1 genindeki 10 tekrar allelinin belirtilerin şiddeti ve metilfenidat yanıtı ile ilişkisi de incelenmiştir. Winsberg ve Comings DEHB'li çocuklarda 9/10 genotipinin daha fazla dopamin taşıyıcısı bağlanmasıyla ve daha iyi metilfenidat yanıtıyla ilişkili olduğunu bildirmişlerdir.…”