Misener V L, Luca P, Azeke O, Crosbie J, Waldman I, Tannock R, Roberts W, Malone M, Schachar R, Ickowicz A, Kennedy J L, Barr C L
Cell and Molecular Biology Division, Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
Mol Psychiatry. 2004 May;9(5):500-9. doi: 10.1038/sj.mp.4001440.
Attention-deficit/hyperactivity disorder (ADHD) has a strong genetic basis, and evidence from human and animal studies suggests the dopamine receptor D1 gene, DRD1, to be a good candidate for involvement. Here, we tested for linkage of DRD1 to ADHD by examining the inheritance of four biallelic DRD1 polymorphisms [D1P.5 (-1251HaeIII), D1P.6 (-800HaeIII), D1.1 (-48DdeI) and D1.7 (+1403Bsp1286I)] in a sample of 156 ADHD families. Owing to linkage disequilibrium between alleles at the four markers, only three haplotypes are common in our sample. Using the transmission/disequilibrium test (TDT), we observed a strong bias for transmission of Haplotype 3 (1.1.1.2) from heterozygous parents to their affected children (P=0.008). Furthermore, using quantitative trait TDT analyses, we found significant and positive relationships between Haplotype 3 transmission and the inattentive symptoms, but not the hyperactive/impulsive symptoms, of ADHD. These findings support the proposed involvement of DRD1 in ADHD, and implicate Haplotype 3, in particular, as containing a potential risk factor for the inattentive symptom dimension of the disorder. Since none of the four marker alleles comprising Haplotype 3 is predicted to alter DRD1 function, we hypothesize that a functional DRD1 variant, conferring susceptibility to ADHD, is on this haplotype. To search for such a variant we screened the DRD1 coding region, by sequencing, focusing on the children who showed preferential transmission of Haplotype 3. DNA from 41 children was analysed, and no sequence variations were identified, indicating that the putative DRD1 risk variant for ADHD resides outside of the coding region of the gene.
注意缺陷多动障碍（ADHD）具有很强的遗传基础，来自人类和动物研究的证据表明多巴胺受体D1基因（DRD1）是一个可能与之相关的良好候选基因。在此，我们通过检测156个ADHD家庭样本中四个双等位基因DRD1多态性位点[D1P.5（-1251HaeIII）、D1P.6（-800HaeIII）、D1.1（-48DdeI）和D1.7（+1403Bsp1286I）]的遗传情况，来测试DRD1与ADHD之间的连锁关系。由于这四个标记位点的等位基因之间存在连锁不平衡，在我们的样本中只有三种单倍型是常见的。使用传递不平衡检验（TDT），我们观察到单倍型3（1.1.1.2）从杂合子父母向其患病子女的传递存在强烈偏差（P = 0.008）。此外，通过定量性状TDT分析，我们发现单倍型3的传递与ADHD的注意力不集中症状之间存在显著的正相关关系，但与多动/冲动症状无关。这些发现支持了DRD1参与ADHD的观点，尤其表明单倍型3包含该疾病注意力不集中症状维度的潜在风险因素。由于构成单倍型3的四个标记等位基因均未被预测会改变DRD1的功能，我们推测在这个单倍型上存在一个导致ADHD易感性的功能性DRD1变体。为了寻找这样的变体，我们通过测序筛选了DRD1编码区，重点关注那些显示出单倍型3优先传递的儿童。对41名儿童的DNA进行了分析，未发现序列变异，这表明ADHD假定的DRD1风险变体位于该基因的编码区之外。
