Terwilliger Joseph D, Hiekkalinna Tero
Department of Genetics and Development, Columbia University, New York, NY, USA.
Eur J Hum Genet. 2006 Apr;14(4):426-37. doi: 10.1038/sj.ejhg.5201583.
The International HapMap Project was proposed in order to quantify linkage disequilibrium (LD) relationships among human DNA polymorphisms in an assortment of populations, in order to facilitate the process of selecting a minimal set of markers that could capture most of the signal from the untyped markers in a genome-wide association study. The central dogma can be summarized by the argument that if a marker is in tight LD with a polymorphism that directly impacts disease risk, as measured by the metric r(2), then one would be able to detect an association between the marker and disease with sample size that was increased by a factor of 1/r(2) over that needed to detect the effect of the functional variant directly. This "fundamental theorem" holds, however, only if one assumes that the LD between loci and the etiological effect of the functional variant are independent of each other, that they are statistically independent of all other etiological factors (in exposure and action), that sampling is prospective, and that the estimates of r(2) are accurate. None of these are standard operating assumptions, however. We describe the ramifications of these implicit assumptions, and provide simple examples in which the effects of a functional variant could be unequivocally detected if it were directly genotyped, even as markers in high LD with the functional variant would never show association with disease, even in infinite sample sizes. Both theoretical and empirical refutation of the central dogma of genome-wide association studies is thus presented.
国际人类基因组单体型图计划（The International HapMap Project）的提出，是为了量化不同人群中人类DNA多态性之间的连锁不平衡（LD）关系，以便在全基因组关联研究中，有助于选择一组最小的标记物，从而能够从未分型的标记物中捕获大部分信号。中心法则可以概括为这样一种观点：如果一个标记物与一个直接影响疾病风险的多态性处于紧密连锁不平衡状态，用r(2)这个指标来衡量，那么与直接检测功能变异体的效应相比，检测该标记物与疾病之间的关联所需的样本量只需增加1/r(2)倍。然而，只有在假设基因座之间的连锁不平衡与功能变异体的病因效应相互独立、它们在统计学上与所有其他病因因素（在暴露和作用方面）相互独立、抽样是前瞻性的以及r(2)的估计是准确的情况下，这个“基本定理”才成立。然而，这些都不是标准的操作假设。我们描述了这些隐含假设的影响，并提供了一些简单的例子，在这些例子中，如果直接对功能变异体进行基因分型，就可以明确检测到其效应，即使与功能变异体处于高连锁不平衡状态的标记物，即使在样本量无限大的情况下，也永远不会显示出与疾病的关联。因此，本文提出了对全基因组关联研究中心法则的理论和实证反驳。
