Halleland H, Lundervold A J, Halmøy A, Haavik J, Johansson S
Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
Am J Med Genet B Neuropsychiatr Genet. 2009 Apr 5;150B(3):403-10. doi: 10.1002/ajmg.b.30831.
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). All 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.
有研究表明，注意力缺陷多动障碍（ADHD）的症状与前额叶皮质中多巴胺水平较低有关。儿茶酚-O-甲基转移酶（COMT）可降解多巴胺和其他儿茶酚胺，该酶对这个脑区的单胺信号传导很重要，但ADHD中功能性Val158Met（rs4680）多态性的基因研究结果并不一致。然而，最近有研究表明，常见的同义COMT变体也可通过影响基因表达来调节COMT的总酶活性 [纳克利等人（2006年）；《科学》314(5807):1930 - 1933]。因此，我们推测，与单独的Val158Met多态性相比，单倍型分析可能会揭示更多关于COMT与ADHD症状之间的关联。对435名临床诊断为ADHD的成年受试者和383名对照者进行了rs6269、rs4633、rs4818和rs4680这几个单核苷酸多态性（SNP）的基因分型，这些SNP可标记常见的假定功能性COMT单倍型，并分析其与ADHD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的关联。所有标记物都显示出与多动/冲动量表有相关趋势，在标记物rs6269处达到峰值（P = 0.007）。单倍型分析表明，rs6269风险等位基因标记了推测的高COMT活性单倍型，在我们的样本中，该单倍型与最高的多动/冲动得分相关（P = 0.01）。我们的结果还表明，与之前描述的中度和低度活性单倍型相关的多动/冲动得分呈逐步下降趋势。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验证这一假设的重要性。
