DRD2 haplotypes containing the TaqI A1 allele: implications for alcoholism research.
DRD2 haplotypes containing the TaqI A1 allele: implications for alcoholism research.
复制标题
DOI：
10.1111/j.1530-0277.1996.tb01674.x
复制
发表时间：
1996-06
期刊：
影响因子：
--
通讯作者：
Kenneth K. Kidd;A. Pakstis;C. Castiglione;J. Kidd;W. Speed;David Goldman;W. Knowler;R. Lu;Batsheva Bonne-Tamir
中科院分区：
文献类型：
--
作者：
Kenneth K. Kidd;A. Pakstis;C. Castiglione;J. Kidd;W. Speed;David Goldman;W. Knowler;R. Lu;Batsheva Bonne-Tamir
近年来，多巴胺D2受体(DRD2)基因在酒精中毒病因学中的可能作用一直是人们关注的焦点。这些文献现在包含了一系列具有积极和消极结论的关联研究。许多研究认为酒精中毒与Taq1“A”位点的DRD2*A1等位基因之间存在正相关，但各种方法缺陷削弱了这一论断。尽管有否定结果的研究更多地来自使用更好的分析方法的研究，但令人满意的解决DRD2基因变异是否在酒精中毒的病因中发挥作用的问题不太可能来自到目前为止进行的此类额外研究；对DRD2的群体遗传学和DRD2等位基因的系统起源的更彻底的理解所启发的方法是一种替代方案。如果DRD2基因座的遗传变异影响对酒精中毒的易感性，那么这种变异有一个突变和进化史，可以借助于DRD2基因座已被发现的各种遗传多态来追踪。在这项研究中，位于DRD2的第三个Taq1限制性片段长度多态，即Taq1“D”位点，已被转换为基于聚合酶链式反应的分型，并在来自世界各地的22个人群中测定了其频率。构建了由Taq1“B”和“A”位点的多态以及内含子2的短串联重复序列多态定义的单倍型，并检测了所有22个群体含有DRD2*A1等位基因的单倍型的多样性。通过对其他高等灵长类动物的同源区域进行测序，也确定了这三个Taq1基因的祖先起源。由于欧洲、中东和非洲起源的群体中含有A1的单倍型在群体内和群体间显示出相当大的多样性，因此在从世界这些地区派生的群体中进行适当设计的关联研究需要使用单倍型，而不是单一的等位基因系统，并且需要使用适当的方法来补偿几乎不可能在遗传上匹配无关的对照样本。
In recent years, a possible role of the dopamine D2 receptor (DRD2) locus in the etiology of alcoholism has been the focus of considerable attention. The literature now contains a mix of association studies with positive and negative conclusions. Various methodological flaws undermine the claims in many of the studies that conclude a positive association exists between alcoholism and the DRD2*A1 allele at the Taql "A" site. Although the studies with negative findings have more often come from studies using better analytic methodology, satisfactory resolution of whether or not genetic variation at the DRD2 locus plays some role in the etiology of alcoholism is unlikely to come from additional studies of the kind conducted thus far; an approach enlightened by a more thorough understanding of the population genetics of DRD2 and the phylogenetic origins of the DRD2 alleles is one alternative. If genetic variation at the DRD2 locus affects susceptibility to alcoholism, then such variation has a mutational and evolutionary history that can be traced with the aid of the various genetic polymorphisms that have been identified at the DRD2 locus. In this study, a third Taql restriction fragment-length polymorphism at DRD2, the Taql "D" site, has been converted to polymerase chain reaction-based typing and its frequencies determined in 22 populations from around the world. Haplotypes defined by the polymorphisms at the Taql "B" and "A" sites, and the short tandem repeat polymorphism in intron 2 have been constructed and the diversity of haplotypes containing the DRD2*A1 allele examined for all 22 populations. The ancestral origins of the three Taql polymorphisms have also been determined by sequencing the homologous regions in other higher primates. Because A1-containing haplotypes in populations of European, Middle Eastern, and African origin show considerable diversity within and among populations, properly designed association studies in populations descended from those areas of the world need to use haplotypes, not a single allelic system, and need to use appropriate methods to compensate for the near impossibility of genetically matching unrelated control samples.