Tong Janette H S, Cummins Tarrant D R, Johnson Beth P, McKinley Leigh-Anne, Pickering Hayley E, Fanning Peter, Stefanac Nicole R, Newman Daniel P, Hawi Ziarih, Bellgrove Mark A
Monash University, School of Psychological Sciences, Melbourne, Victoria, Australia.
Am J Med Genet B Neuropsychiatr Genet. 2015 Mar;168B(2):89-96. doi: 10.1002/ajmg.b.32283. Epub 2015 Feb 5.
Previous genetic studies have postulated that attention deficit hyperactivity disorder (ADHD) should be regarded as the extreme end of a set of behavioural traits that can be continuously measured in the general population. The current study adopted a quantitative trait approach to examine the relationship between dopamine gene variants and self-reported ADHD symptoms in 517 nonclinical adults. Although genetic associations with variants of both the dopamine transporter (DAT1; SLC6A3) and D4 receptor (DRD4) genes have been reliably reported in children, results in adults are less consistent. We probed two potentially functional variable number of tandem repeat (VNTR) polymorphisms in the 3'UTR and intron 8 of DAT1, the 10-repeat and 6-repeat alleles of which respectively form a haplotype (10/6 DAT1 haplotype) that is associated with childhood ADHD. We also genotyped the exon 3 VNTR of DRD4, the 7-repeat allele of which is also an established risk factor for childhood ADHD. Permutation analysis showed an influence of the 10/6 DAT1 haplotype on both CAARS-G and CAARS-H (DSM-IV ADHD Symptoms Total and ADHD Index respectively), such that ADHD symptom scores increased with each additional copy of the 10/6 DAT1 haplotype. This result survived corrections for multiple comparisons both at the level of genotype and phenotype. A nominal association with CAARS-G was also found for the 7-repeat allele of the DRD4 VNTR however this did not survive multiple comparison correction. Our results provide further support for the influence of variation in the 10/6 DAT1 haplotype and individual differences in ADHD symptoms in adults.
以往的基因研究推测，注意力缺陷多动障碍（ADHD）应被视为一组可在普通人群中持续测量的行为特征的极端表现。本研究采用数量性状方法，对517名非临床成年人中多巴胺基因变异与自我报告的ADHD症状之间的关系进行了研究。尽管在儿童中已可靠报道了多巴胺转运体（DAT1；SLC6A3）和D4受体（DRD4）基因变异的遗传关联，但在成年人中的结果却不太一致。我们探究了DAT1基因3'非翻译区（3'UTR）和第8内含子中两个潜在功能性的可变串联重复序列（VNTR）多态性，其中10重复和6重复等位基因分别形成一种单倍型（10/6 DAT1单倍型），该单倍型与儿童ADHD相关。我们还对DRD4基因外显子3的VNTR进行了基因分型，其7重复等位基因也是儿童ADHD的既定风险因素。置换分析显示10/6 DAT1单倍型对CAARS - G和CAARS - H（分别为DSM - IV ADHD症状总分和ADHD指数）均有影响，即ADHD症状评分随10/6 DAT1单倍型的额外拷贝数增加而升高。这一结果在基因型和表型水平的多重比较校正后仍然成立。对于DRD4 VNTR的7重复等位基因，也发现与CAARS - G存在名义上的关联，但在多重比较校正后未通过检验。我们的结果为10/6 DAT1单倍型变异对成年人ADHD症状个体差异的影响提供了进一步支持。
