Ohashi J, Tokunaga K
Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Japan.
J Hum Genet. 2001;46(8):478-82. doi: 10.1007/s100380170048.
Genome-wide association studies using a dense map of single nucleotide polymorphism (SNP) markers seem to enable us to detect a number of complex disease genes. In such indirect association studies, whether susceptibility genes can be detected is dependent not only on the degree of linkage disequilibrium between the disease variant and the SNP marker but also on the difference in their allele frequencies. These factors, as well as penetrance of the disease variant, influence the statistical power of such approaches. However, the power of indirect association studies is not well understood. We calculated the number of individuals necessary for the detection of the disease variant in both direct and indirect association studies with a case-control design. The result shows that a remarkable reduction in the statistical power of indirect studies, compared with that of direct ones, is unavoidable in the genome-wide screening of complex disease genes. If there is a large difference in allele frequency between the disease variant and the marker, the disease variant cannot be detected. Because the frequency of the disease variant is unknown, SNP markers with various allele frequencies, or a large number of SNP markers, must be used in indirect association studies. However, if the number of SNP markers is increased, the obtained P value may not reach the significance level due to the Bonferroni adjustment. Thus, to test a possible association between functional variants and a complex disease directly, we should identify such SNPs in as many genes as possible for use in genome-wide association studies.
使用单核苷酸多态性（SNP）标记的高密度图谱进行全基因组关联研究，似乎能让我们检测出许多复杂疾病基因。在这类间接关联研究中，能否检测到易感基因不仅取决于疾病变异与SNP标记之间的连锁不平衡程度，还取决于它们等位基因频率的差异。这些因素以及疾病变异的外显率，都会影响此类方法的统计效力。然而，间接关联研究的效力尚未得到充分理解。我们计算了在病例对照设计的直接和间接关联研究中检测疾病变异所需的个体数量。结果表明，在复杂疾病基因的全基因组筛查中，与直接研究相比，间接研究的统计效力显著降低是不可避免的。如果疾病变异与标记之间的等位基因频率存在较大差异，就无法检测到疾病变异。由于疾病变异的频率未知，在间接关联研究中必须使用具有不同等位基因频率的SNP标记，或者大量的SNP标记。然而，如果增加SNP标记的数量，由于Bonferroni校正，所获得的P值可能无法达到显著性水平。因此，为了直接检验功能变异与复杂疾病之间可能存在的关联，我们应该在尽可能多的基因中鉴定此类SNP，以用于全基因组关联研究。
