Nielsen Dahlia M, Suchindran Sunil, Smith Christopher P
Program in Statistical Genetics, Department of Genetics, North Carolina State University, Raleigh, NC 27695-7566, USA.
Genet Epidemiol. 2008 Sep;32(6):546-52. doi: 10.1002/gepi.20328.
A substantial amount of effort has been expended recently towards the identification and evaluation of tag single nucleotide polymorphisms; markers that, due to linkage disequilibrium (LD) patterns in the genome, are able to act as "proxies" for other polymorphic sites. As such, these tag markers are assumed to capture, on their own, a large proportion of the genetic variation contributed by a much greater number of polymorphic sites. One important consequence of this is the potential ability to reduce the cost of genotyping in an association study without a corresponding loss of power. This application carries an implicit assumption that strong LD between markers implies high correlation between the accompanying association test results, so that once a tag marker is evaluated for association, its outcome will be representative of all the other markers for which it serves as proxy. We examined this assumption directly. We find that in the null hypothesis situation, where there is no association between the markers and the phenotype, the relationship between LD and the correlation between association test outcomes is clear, though it is not always ideal. In the alternative case, when genetic association does exist in the region, the relationship becomes much more complex. Here, reasonably high LD between markers does not necessarily imply that the association test result of one marker is a direct substitute for that of the other. In these cases, eliminating one of these markers from the set to be genotyped in an association study will lead to a reduction in overall power.
最近，人们付出了大量努力来识别和评估标签单核苷酸多态性；由于基因组中的连锁不平衡（LD）模式，这些标记能够作为其他多态性位点的“替代物”。因此，这些标签标记被认为自身就能捕获大量由更多多态性位点所贡献的遗传变异。这样做的一个重要结果是，在不相应损失检验效能的情况下，有可能降低关联研究中的基因分型成本。这种应用隐含着一个假设，即标记之间的强连锁不平衡意味着伴随的关联检验结果之间具有高度相关性，因此一旦评估了一个标签标记的关联性，其结果将代表它所替代的所有其他标记。我们直接检验了这个假设。我们发现，在零假设情况下，即标记与表型之间不存在关联时，连锁不平衡与关联检验结果之间的相关性是明确的，尽管并不总是理想的。在另一种情况下，当该区域存在基因关联时，这种关系就变得更加复杂。在这里，标记之间相当高的连锁不平衡并不一定意味着一个标记的关联检验结果可以直接替代另一个标记的结果。在这些情况下，在关联研究中从待基因分型的标记集中剔除其中一个标记将导致总体检验效能降低。
