Curran Sarah, Purcell Shaun, Craig Ian, Asherson Philip, Sham Pak
MRC Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, De Crespigny Park, London, United Kingdom.
Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134B(1):42-7. doi: 10.1002/ajmg.b.30118.
Molecular studies of attention deficit hyperactivity disorder (ADHD) have identified susceptibility genes for the categorically diagnosed disorder using operational diagnostic criteria. Here, we take a QTL approach to mapping genes for ADHD using a composite continuous index of ADHD behavior in a large epidemiological sample. Previous studies of clinical ADHD suggest that two functional polymorphisms in the serotonin transporter gene (SLC6A4), one in the 5'-regulatory region of the gene (5-HTTLPR) and the other a VNTR (5-HTTVNTR) in the second intron, as well as a single nucleotide polymorphism in the 3'-untranslated region (3'-UTR SNP), may be associated with the disorder. Here, we investigate these polymorphisms as well as an additional ten SNPs spread across the gene. We found significant association with the long (L) allele of the 5-HTTLPR; P = 0.019, but neither the 5-HTTVNTR nor the 3'-UTR SNP were significantly associated. Significant associations (P < 0.05) were found for a further 5 the 10 other markers tested. We found evidence for two haplotype blocks spanning the region. We found strong evidence for association with the first haplotype block (comprised of four markers), with the significance of a combined primary and secondary test of association reaching an empirical P value = 0.0054 for the global test and an empirical P value = 0.00081 for the largest local test. Thus, we show here that SLC6A4, which has a major influence on brain serotonin availability, may be a QTL for ADHD.
注意力缺陷多动障碍（ADHD）的分子研究已经通过操作诊断标准确定了该分类诊断疾病的易感基因。在此，我们采用数量性状基因座（QTL）方法，在一个大型流行病学样本中，使用ADHD行为的综合连续指标来定位ADHD相关基因。先前对临床ADHD的研究表明，血清素转运体基因（SLC6A4）中的两个功能多态性，一个在基因的5'调控区域（5-HTTLPR），另一个是位于第二个内含子的可变数目串联重复序列（5-HTTVNTR），以及3'非翻译区域的一个单核苷酸多态性（3'-UTR SNP），可能与该疾病有关。在此，我们研究这些多态性以及分布在该基因上的另外十个单核苷酸多态性。我们发现与5-HTTLPR的长（L）等位基因存在显著关联；P = 0.019，但5-HTTVNTR和3'-UTR SNP均无显著关联。在另外测试的10个标记中，有5个发现了显著关联（P < 0.05）。我们发现有证据表明该区域存在两个单倍型块。我们发现有强有力的证据表明与第一个单倍型块（由四个标记组成）存在关联，联合的一级和二级关联检验的显著性对于全局检验达到经验P值 = 0.0054，对于最大的局部检验达到经验P值 = 0.00081。因此，我们在此表明，对大脑血清素可用性有主要影响的SLC6A4可能是ADHD的一个QTL。
