Brookes K J, Xu X, Anney R, Franke B, Zhou K, Chen Wai, Banaschewski T, Buitelaar J, Ebstein R, Eisenberg J, Gill M, Miranda A, Oades R D, Roeyers H, Rothenberger A, Sergeant J, Sonuga-Barke E, Steinhausen H-C, Taylor E, Faraone S V, Asherson P
MRC Social Genetic Developmental and Psychiatry Centre, Institute of Psychiatry, London, UK.
Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1519-23. doi: 10.1002/ajmg.b.30782.
Multiple studies have reported an association between attention deficit hyperactivity disorder (ADHD) and the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region (3'UTR) of the dopamine transporter gene (DAT1). Yet, recent meta-analyses of available data find little or no evidence for this association; although there is strong evidence for heterogeneity between datasets. This pattern of findings could arise for several reasons including the presence of relatively rare risk alleles on common haplotype backgrounds or the functional interaction of two or more loci within the gene. We previously described the importance of a specific haplotype at the 3' end of DAT1, as well as the identification of associated single nucleotide polymorphisms (SNPs) within or close to 5' regulatory sequences. In this study we replicate the association of SNPs at the 5' end of the gene and identify a specific risk haplotype spanning the 5' and 3' markers. These findings indicate the presence of at least two loci associated with ADHD within the DAT1 gene and suggest that either additive or interaction effects of these two loci on the risk for ADHD. Overall these data provide further evidence that genetic variants of the dopamine transporter gene confer an increased risk for ADHD.
多项研究报告称，注意力缺陷多动障碍（ADHD）与多巴胺转运体基因（DAT1）3'非翻译区（3'UTR）可变数目串联重复序列（VNTR）多态性的10次重复等位基因之间存在关联。然而，最近对现有数据的荟萃分析几乎没有发现这种关联的证据；尽管各数据集之间存在明显的异质性证据。这种研究结果模式可能有多种原因，包括常见单倍型背景上存在相对罕见的风险等位基因，或该基因内两个或多个位点的功能相互作用。我们之前描述了DAT1 3'端特定单倍型的重要性，以及在5'调控序列内或附近相关单核苷酸多态性（SNP）的鉴定。在本研究中，我们重复了该基因5'端SNP的关联，并鉴定出一个跨越5'和3'标记的特定风险单倍型。这些发现表明DAT1基因内至少存在两个与ADHD相关的位点，并提示这两个位点对ADHD风险的加性或相互作用效应。总体而言，这些数据进一步证明多巴胺转运体基因的遗传变异会增加患ADHD的风险。
