Xiong M, Guo S W
Human Genetics Center, Health Science Center, University of Texas-Houston, Houston, Tex., USA.
Hum Hered. 1998 Nov-Dec;48(6):295-312. doi: 10.1159/000022821.
Despite growing interest in the use of transmission/disequilibrium test (TDT)-type analysis in association studies, there has been surprisingly scant attention paid to the issues as to what factors affect the power of the TDT for linkage detection. We demonstrate in this paper that the power is a function of several genetic parameters including the recombination fraction, penetrance, the age of mutant disease allele, marker allele frequency, recurrent mutation rates at marker and/or disease locus, and initial linkage disequilibrium. In general, TDT has greater power to detect linkage for a 'recessive'-type model than for a 'dominant'-type model. Its power also is higher when there is greater differential in marker allele frequency between disease and normal chromosomes. And since the presence of marker mutation and/or recurrent mutation at the disease locus, or the age of disease mutation, or the initial incomplete linkage disequilibrium, all hasten the process to reach linkage equilibrium, all of them can affect the power of TDT to detect linkage. The effect of marker mutation rate or the mutation rate at the disease locus can be minimal if mutation rates are low. The results on the impact of recombination fraction and of age of mutation on the power of TDT in linkage detection seem to be disheartening for gene mappers of complex diseases: for a disease with small genetic influence, a vastly large sample size is needed to detect the linkage, if the marker is not very close to the disease locus. This is particularly true if the disease is 'old'.
尽管在关联研究中使用传递/不平衡检验（TDT）类型分析的兴趣日益浓厚，但令人惊讶的是，对于影响TDT连锁检测效能的因素问题，人们关注甚少。我们在本文中证明，效能是几个遗传参数的函数，这些参数包括重组率、外显率、突变疾病等位基因的年龄、标记等位基因频率、标记和/或疾病位点的复发突变率以及初始连锁不平衡。一般来说，对于“隐性”模型，TDT检测连锁的效能比“显性”模型更高。当疾病染色体和正常染色体之间的标记等位基因频率差异更大时，其效能也更高。而且，由于标记突变和/或疾病位点的复发突变的存在，或者疾病突变的年龄，或者初始不完全连锁不平衡，都会加速达到连锁平衡的过程，所有这些都会影响TDT检测连锁的效能。如果突变率较低，标记突变率或疾病位点的突变率的影响可能最小。重组率和突变年龄对TDT连锁检测效能的影响结果，对于复杂疾病的基因定位者来说似乎令人沮丧：对于遗传影响较小的疾病，如果标记与疾病位点不太接近，需要非常大的样本量才能检测到连锁。如果疾病是“古老的”，情况尤其如此。
