Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada.
PLoS One. 2012;7(11):e49616. doi: 10.1371/journal.pone.0049616. Epub 2012 Nov 20.
Despite strong pharmacological evidence implicating the norepinephrine transporter in ADHD, genetic studies have yielded largely insignificant results. We tested the association between 30 tag SNPs within the SLC6A2 gene and ADHD, with stratification based on maternal smoking during pregnancy, an environmental factor strongly associated with ADHD.
Children (6-12 years old) diagnosed with ADHD according to DSM-IV criteria were comprehensively evaluated with regard to several behavioral and cognitive dimensions of ADHD as well as response to a fixed dose of methylphenidate (MPH) using a double-blind placebo controlled crossover trial. Family-based association tests (FBAT), including categorical and quantitative trait analyses, were conducted in 377 nuclear families.
A highly significant association was observed with rs36021 (and linked SNPs) in the group where mothers smoked during pregnancy. Association was noted with categorical DSM-IV ADHD diagnosis (Z=3.74, P=0.0002), behavioral assessments by parents (CBCL, P=0.00008), as well as restless-impulsive subscale scores on Conners'-teachers (P=0.006) and parents (P=0.006). In this subgroup, significant association was also observed with cognitive deficits, more specifically sustained attention, spatial working memory, planning, and response inhibition. The risk allele was associated with significant improvement of behavior as measured by research staff (Z=3.28, P=0.001), parents (Z=2.62, P=0.009), as well as evaluation in the simulated academic environment (Z=3.58, P=0.0003).
By using maternal smoking during pregnancy to index a putatively more homogeneous group of ADHD, highly significant associations were observed between tag SNPs within SLC6A2 and ADHD diagnosis, behavioral and cognitive measures relevant to ADHD and response to MPH. This comprehensive phenotype/genotype analysis may help to further understand this complex disorder and improve its treatment. Clinical trial registration information - Clinical and Pharmacogenetic Study of Attention Deficit with Hyperactivity Disorder (ADHD); www.clinicaltrials.gov; NCT00483106.
尽管有强有力的药理学证据表明去甲肾上腺素转运体与 ADHD 有关，但遗传研究的结果大多没有意义。我们检测了 SLC6A2 基因内 30 个标记 SNP 与 ADHD 的关联，并根据母亲怀孕期间吸烟这一与 ADHD 强烈相关的环境因素进行了分层。
根据 DSM-IV 标准诊断为 ADHD 的儿童（6-12 岁）接受了全面评估，包括 ADHD 的多个行为和认知维度，以及使用双盲安慰剂对照交叉试验对固定剂量的哌醋甲酯（MPH）的反应。在 377 个核心家庭中进行了基于家庭的关联测试（FBAT），包括分类和数量性状分析。
在母亲怀孕期间吸烟的组中，观察到 rs36021（及其连锁 SNP）高度显著关联。在 DSM-IV ADHD 诊断的分类（Z=3.74，P=0.0002）、父母的行为评估（CBCL，P=0.00008）以及康纳斯老师-家长的多动冲动子量表评分（P=0.006）中也观察到了关联。在这个亚组中，与认知缺陷也有显著关联，特别是持续注意力、空间工作记忆、计划和反应抑制。风险等位基因与研究人员（Z=3.28，P=0.001）、父母（Z=2.62，P=0.009）以及模拟学术环境中的评估（Z=3.58，P=0.0003）所测量的行为显著改善有关。
通过使用母亲怀孕期间吸烟来标记一个假定更同质的 ADHD 群体，我们观察到 SLC6A2 内的标记 SNP 与 ADHD 诊断、与 ADHD 相关的行为和认知测量以及对 MPH 的反应之间存在高度显著的关联。这种综合的表型/基因型分析可能有助于进一步理解这种复杂的疾病，并改善其治疗。临床试验注册信息-注意力缺陷多动障碍（ADHD）的临床和遗传药理学研究；www.clinicaltrials.gov；NCT00483106。
