Association Between Catechol O-methyltransferase [COMT] Haplotypes and Severity of Hyperactivity Symptoms in Adults
Association Between Catechol O-methyltransferase [COMT] Haplotypes and Severity of Hyperactivity Symptoms in Adults
复制标题
DOI：
10.1002/ajmg.b.30831
复制
发表时间：
2009-04-05
影响因子：
2.8
通讯作者：
Johansson, S.
中科院分区：
文献类型：
--
作者：
Halleland, H.;Lundervold, A. J.;Johansson, S.
注意力缺陷多动障碍（ADHD）的症状与前额叶皮层中的低多巴胺水平有关。儿茶酚O-甲基转移酶（COMT），降解多巴胺和其他儿茶酚胺，是重要的单胺信号在这个大脑区域，但遗传研究的功能Val 158 Met（rs 4680）多态性多动症一直不一致。然而，最近显示，常见的同义COMT变体也通过影响基因的表达来调节总COMT酶活性[Nackley等人（2006）; Science 314（5807）：1930-1933]。因此，我们假设单倍型分析可以揭示更多的COMT和ADHD症状之间的关联比单独的Val 158 Met多态性。SNPs rs6269、rs 4633、rs 4818和rs 4680标记了常见的假定功能性COMT单倍型，对435名临床诊断为ADHD的成人受试者和383名对照者进行了基因分型，并分析了与ADHD的相关性以及成人ADHD自我报告量表（ASRS）中的多动/冲动和注意力不集中维度。AD标志物显示出与多动/冲动量表相关的趋势，在标志物rs6269处达到峰值（P = 0.007）。单倍型分析显示rs6269风险等位基因标记了建议的高COMT活性单倍型，这与我们样本中最高的多动/冲动评分相关（P = 0.01）。我们的研究结果还表明，有一个逐步减少的多动/冲动得分与建议的中，低活动的单倍型先前描述。总之，我们认为COMT单倍型变异主要与ADHD的多动/冲动维度相关，并指出在未来研究中检验这一假设的重要性。(C)2008 Wiley-Liss，Inc.
It has been suggested that symptoms of attention-deficit/hyperactivity disorder (ADHD) is related to low dopamine levels in the prefrontal cortex. The enzyme catechol O-methyltransferase (COMT), which degrades dopamine and other catecholamines, is important for monoamine signaling in this brain-region, but genetic studies of the functional Val158Met (rs4680) polymorphism in ADHD have been inconsistent. However, recently it was shown that also common synonymous COMT variants modulate total COMT enzymatic activity by affecting the expression of the gene [Nackley et al. (2006); Science 314(5807):1930-1933]. We therefore hypothesized that analysis of haplotypes could reveal more about the association between COMT and ADHD symptoms than the Val158Met polymorphism alone. SNPs rs6269, rs4633, rs4818, and rs4680, tagging the common putative functional COMT haplotypes, were genotyped in 435 adult subjects with a clinical diagnosis of ADHD and 383 controls and analyzed for association with ADHD and the hyperactivity/impulsivity and inattention dimensions from the Adult ADHD Self-Report Scale (ASRS). AD markers showed a trend for association with the hyperactivity/impulsivity scale, peaking at marker rs6269 (P = 0.007). Haplotype analysis revealed that the rs6269 risk allele tags the suggested high COMT-activity haplotype, which is associated with the highest hyperactivity/impulsivity score in our sample (P = 0.01). Our results also suggest that there is a stepwise decreased hyperactivity/impulsivity score associated with the proposed mid and low activity haplotypes described previously. In conclusion, we suggest that COMT haplotype variation is associated primarily with the hyperactivity/impulsivity dimension of ADHD and point to the importance of testing this hypothesis in future studies. (C) 2008 Wiley-Liss, Inc.