Manor Iris, Laiba Efrat, Eisenberg Jacques, Meidad Sheera, Lerer Elad, Israel Salomon, Gritsenko Inga, Tyano Sam, Faraone Stephen V, Ebstein Richard P
ADHD Unit, Geha Mental Health Center Petach Tikva, Israel.
Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1501-8. doi: 10.1002/ajmg.b.30702.
The main objective of this study was to examine neuropsychological mechanisms mediating the association between tryptophan hydroxylase 2 (TPH2) and attention deficit hyperactivity disorder (ADHD). A continuous performance test (T.O.V.A.) was administered to 344 participants diagnosed with DSM IV ADHD who were also genotyped for eight TPH2 intronic SNPs. Association between TPH2 (single SNPs and haplotypes), ADHD, and performance on the T.O.V.A. were tested using robust family-based association tests as implemented in two statistical genetic programs: UNPHASED and PBAT. Association was only observed between an eight locus haplotype and ADHD DSM IV combined type III (global P = 0.036). Robust association was observed between TPH2 single SNPs (and haplotypes) and performance on the T.O.V.A., especially Errors of Omission (eight locus haplotypes, global P = 0.038). Significant associations were also observed between TPH2 and improvement (before-after scores) in T.O.V.A. Total Response Variability scores following acute methylphenidate challenge (eight locus haplotypes, global P = 0.009). Using the MFBAT program, significant multivariate association was observed between single SNPs and haplotypes [eight locus haplotypes and all four T.O.V.A. variables (PBAT-GEE P = 0.013)]. The two most common TPH2 eight locus haplotypes were in a Yin Yang configuration and the Yang haplotype was the risk haplotype for both DSM IV ADHD and deficits in neuropsychological performance. The current investigation shows that risk for ADHD conferred by TPH2 variants is partially mediated by serotonergic mechanisms impacting some facets of executive function. Importantly, improvement in T.O.V.A. performance, especially on Response Time Variability, following methylphenidate was also associated with TPH2.
本研究的主要目的是探讨介导色氨酸羟化酶2（TPH2）与注意力缺陷多动障碍（ADHD）之间关联的神经心理学机制。对344名被诊断为DSM-IV ADHD的参与者进行了持续操作测试（T.O.V.A.），这些参与者还针对8个TPH2内含子单核苷酸多态性（SNP）进行了基因分型。使用两个统计遗传程序（UNPHASED和PBAT）中实施的稳健的基于家系的关联测试，检验TPH2（单SNP和单倍型）、ADHD与T.O.V.A.表现之间的关联。仅在一个8位点单倍型与ADHD DSM-IV混合型III之间观察到关联（全局P = 0.036）。在TPH2单SNP（和单倍型）与T.O.V.A.表现之间观察到稳健的关联，尤其是遗漏错误（8位点单倍型，全局P = 0.038）。在急性哌甲酯激发后，TPH2与T.O.V.A.总反应变异性评分的改善（前后评分）之间也观察到显著关联（8位点单倍型，全局P = 0.009）。使用MFBAT程序，在单SNP和单倍型之间观察到显著的多变量关联[8位点单倍型与所有四个T.O.V.A.变量（PBAT-GEE P = 0.013）]。TPH2最常见的两个8位点单倍型呈阴阳构型，阳单倍型是DSM-IV ADHD和神经心理学表现缺陷的风险单倍型。当前研究表明，TPH2变体赋予的ADHD风险部分由影响执行功能某些方面的5-羟色胺能机制介导。重要的是，哌甲酯治疗后T.O.V.A.表现的改善，尤其是反应时间变异性方面的改善，也与TPH2相关。
