Hasler R, Salzmann A, Bolzan T, Zimmermann J, Baud P, Giannakopoulos P, Perroud N
Department of Psychiatry, University of Geneva, Geneva, Switzerland,
Neurol Sci. 2015 Jun;36(6):861-9. doi: 10.1007/s10072-014-2051-7. Epub 2015 Jan 3.
Attention-deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder often persisting in adulthood. Genetic studies of ADHD mainly focused on the Dopamine Transporter (DAT1) and the Dopamine Receptor 4 (DRD4) genes. Nevertheless, polymorphisms of these genes explain only a small fraction of the assigned risk, suggesting that intermediate dimensions and environmental factors should also be considered. We investigated in 77 adult ADHD subjects compared to 474 controls, how polymorphisms within the genes coding for DAT1 (40-bp VNTR in 3'UTR), the Dopamine Receptor 2 (DRD2) (rs1799732) and DRD4 (48-bp VNTR in exon 3), may modulate the expression of the disorder. By genotyping DAT1, we detected a new 9.5R allele showing a deletion of 40 bp and also an insertion of 19 bp compared to the 10R allele. This novel allele was found to be significantly protective for ADHD (p < 0.0001). Another significant difference was found in the distribution of DRD4 48-bp VNTR 6R allele when comparing patients and controls (p = 0.0007). In addition significant results were also found for DAT1 9.5R allele, which was associated with impulsiveness (p = 1.98 × 10(-4)) and trait anger scores (p = 7.66 × 10(-4)). Moreover, impulsiveness scores were partly modulated by an interaction between the DRD4 48-bp VNTR 6R allele and childhood maltreatment (p = 0.01), however, this result did not resist correction for multiple comparisons. Altogether, our results show the putative involvement of DAT1 and DRD4 genes in the aetiology of ADHD with a main role in modulation of key dimensions of the disorder.
注意缺陷多动障碍（ADHD）是一种具有高度遗传性的神经发育障碍，常在成年期持续存在。ADHD的基因研究主要集中在多巴胺转运体（DAT1）和多巴胺受体4（DRD4）基因上。然而，这些基因的多态性仅解释了一小部分既定风险，这表明还应考虑中间维度和环境因素。我们对77名成年ADHD患者与474名对照进行了研究，以探究编码DAT1（3'非翻译区的40 bp可变数目串联重复序列）、多巴胺受体2（DRD2）（rs1799732）和DRD4（外显子3中的48 bp可变数目串联重复序列）的基因内的多态性如何调节该疾病的表达。通过对DAT1进行基因分型，我们检测到一个新的9.5R等位基因，与10R等位基因相比，它缺失了40 bp并插入了19 bp。发现这个新等位基因对ADHD具有显著的保护作用（p < 0.0001）。在比较患者和对照时，还发现DRD4 48 bp可变数目串联重复序列6R等位基因的分布存在显著差异（p = 0.0007）。此外，还发现DAT1 9.5R等位基因有显著结果，它与冲动性（p = 1.98 × 10⁻⁴）和特质愤怒得分（p = 7.66 × 10⁻⁴）相关。此外，冲动性得分部分受到DRD4 48 bp可变数目串联重复序列6R等位基因与童年期虐待之间相互作用的调节（p = 0.01），然而，该结果在多重比较校正后不成立。总之，我们的结果表明DAT1和DRD4基因可能参与了ADHD的病因学，在调节该疾病的关键维度中起主要作用。
