Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder
Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder
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DOI：
10.1038/sj.mp.4001734
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发表时间：
2005-12-01
影响因子：
11
通讯作者：
Lesch, KP
中科院分区：
文献类型：
--
作者：
Walitza, S;Renner, TJ;Lesch, KP
注意力缺陷多动障碍(ADHD)是儿童时期最常见的行为障碍，具有很强的遗传性。药理学和分子遗传学研究以及动物模型的表征表明，5-羟色胺能功能障碍与ADHD的病理生理学有关。在这里，我们研究了色氨酸羟化酶-2(TPH2)基因的多态变异对ADHD儿童和青少年的影响。TPH2是大脑中合成5-羟色胺(5-HT)的限速酶。我们分析了103个家庭225名受影响儿童的TPH2基因转录控制区及其下游的三个单核苷酸多态(SNPs)。使用系谱不平衡检验评估有一个以上受影响儿童的家庭中的等位基因关联。Tph2‘S调控区的两个SNP存在优先传递(rs4570625，P=0.049；rs11178997，P=0.034)，而内含子2的第三个SNP未检测到优先传递(rs4565946，P=0.3517)。单倍型分析显示调节区SNPs(rs4570625、rs11178997)与注意缺陷多动障碍(ADHD)有很强的相关性(P=0.064)。我们的结果将潜在的功能性TPH2变异与ADHD的病理生理学联系起来，并进一步支持5-羟色胺在与运动活动和认知过程改变相关的障碍中的相关性。
Attention- deficit/ hyperactivity disorder ( ADHD) is the most common behavioral disorder in childhood with substantial heritability. Pharmacological and molecular genetic studies as well as characterization of animal models have implicated serotonergic dysfunction in the pathophysiology of ADHD. Here, we investigated the effect of polymorphic variants in the gene of the tryptophan hydroxylase- 2 ( TPH2), the rate- limiting enzyme of serotonin ( 5- HT) synthesis in the brain, in children and adolescents with ADHD. We analyzed three single nucleotide polymorphisms ( SNPs) in and downstream of the transcriptional control region of the TPH2 gene in 103 families with 225 affected children. Allelic association in families with more than one affected child was assessed using the pedigree disequilibrium test. Preferential transmissions were detected for the two SNPs in TPH2' s regulatory region ( rs4570625, P = 0.049; rs11178997, P = 0.034), but not for the third SNP in intron 2 ( rs4565946, P = 0.3517). Haplotype analysis revealed a strong trend of association between the regulatory region SNPs ( rs4570625, rs11178997) and ADHD ( P = 0.064). Our results link potentially functional TPH2 variations to the pathophysiology of ADHD, and further support the relevance of 5- HT in disorders related to altered motor activity and cognitive processes.