Douglas Hospital Research Centre, Verdun, Que.
J Psychiatry Neurosci. 2012 Feb;37(2):129-37. doi: 10.1503/jpn.110073.
Pharmacologic and animal studies have strongly implicated the norepinephrine transporter (NET) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We conducted a family-based study, with stratification based on sex and subtype, to test the association between 30 tag single-nucleotide polymorphisms (SNPs) within the gene encoding NET (SLC6A2) and ADHD.
Family-based association tests were conducted with the categorical diagnosis of ADHD, as well as quantitative phenotypes of clinical relevance (Conners Global Index for Teachers and Parents, and Child Behavior Checklist measures). Sliding window haplotype analysis was conducted with screening based on conditional power using PBAT.
A previously reported association with rs3785143 was confirmed in this study. Further, extensive association was observed with haplotype blocks, with a differential pattern observed based on sex and subtype. The 5' region of the gene (encompassing haplotype block 1 and including a functional promoter SNP, rs28386840) showed an association with ADHD in girls (irrespective of subtype). A different region of the gene (distributed around haplo-type block 2) was associated with distinct behavioural phenotypes in boys. These findings are correlated with previously reported functional studies of gene variants in SLC6A2.
The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype.
The results obtained in this family-based study suggest that haplotype blocks within different regions of SLC6A2 show differential association with the disorder based on sex and subtype. These associations may have been masked in previous studies when tests were conducted with pooled samples.
药理学和动物研究强烈表明去甲肾上腺素转运体（NET）在注意缺陷/多动障碍（ADHD）的病理生理学中起作用。我们进行了一项基于家庭的研究，根据性别和亚型进行分层，以检验编码 NET（SLC6A2）的基因内 30 个标签单核苷酸多态性（SNP）与 ADHD 之间的关联。
使用 ADHD 的分类诊断以及具有临床相关性的定量表型（教师和家长康纳斯全球指数以及儿童行为检查表测量）进行基于家庭的关联测试。使用 PBAT 基于条件功效进行筛选，进行滑动窗口单体型分析。
本研究证实了先前与 rs3785143 相关的关联。此外，广泛观察到单体型块的关联，并且根据性别和亚型观察到不同的模式。基因的 5'区域（包含单体型块 1 并包括功能性启动子 SNP rs28386840）与女孩的 ADHD 相关（无论亚型如何）。基因的不同区域（分布在单体型块 2 周围）与男孩的不同行为表型相关。这些发现与 SLC6A2 中基因变异的先前报道的功能研究相关。
该研究的最大限制是基于性别然后是亚型进行分层导致的组的规模较小。
这项基于家庭的研究结果表明，SLC6A2 不同区域内的单体型块根据性别和亚型与该疾病显示出不同的关联。当使用 pooled samples 进行测试时，这些关联可能被先前的研究掩盖了。
