Williamson J A, Amos C I
Program in Applied Mathematics, University of Colorado, Boulder 80309, USA.
Genet Epidemiol. 1995;12(2):163-76. doi: 10.1002/gepi.1370120205.
Analysis of genetic linkage between a disease and a marker locus requires specifying a genetic model describing both the inheritance pattern and the gene frequencies of the marker and trait loci. Misspecification of the genetic model is likely for etiologically complex diseases. In previous work we have shown through analytic studies that misspecifying the genetic model for disease inheritance does not lead to excess false-positive evidence for genetic linkage provided the genetic marker alleles of all pedigree members are known, or can be inferred without bias from the data. Here, under various selection or ascertainment schemes we extend these previous results to situations in which the genetic model for the marker locus may be incorrect. We provide sufficient conditions for the asymptotic unbiased estimation of the recombination fraction under the null hypothesis of no linkage, and also conditions for the limiting distribution of the likelihood ratio test for no linkage to be chi-squared. Through simulation studies we document some situations under which asymptotic bias can result when the genetic model is misspecified. Among those situations under which an excess of false-positive evidence for genetic linkage can be generated, the most common is failure to provide accurate estimates of the marker allele frequencies. We show that in most cases false-positive evidence for genetic linkage is unlikely to result solely from the misspecification of the genetic model for disease or trait inheritance.
分析疾病与标记位点之间的遗传连锁需要指定一个遗传模型，该模型既要描述标记位点和性状位点的遗传模式，也要描述它们的基因频率。对于病因复杂的疾病，遗传模型很可能被错误设定。在之前的工作中，我们通过分析研究表明，只要所有家系成员的遗传标记等位基因是已知的，或者可以从数据中无偏差地推断出来，那么错误设定疾病遗传的遗传模型不会导致遗传连锁出现过多的假阳性证据。在此，在各种选择或确定方案下，我们将这些先前的结果扩展到标记位点的遗传模型可能不正确的情况。我们给出了在无连锁的零假设下重组率渐近无偏估计的充分条件，以及无连锁似然比检验的极限分布为卡方分布的条件。通过模拟研究，我们记录了一些在遗传模型被错误设定时可能导致渐近偏差的情况。在那些可能产生过多遗传连锁假阳性证据的情况中，最常见的是未能准确估计标记等位基因频率。我们表明，在大多数情况下，遗传连锁的假阳性证据不太可能仅仅源于疾病或性状遗传的遗传模型被错误设定。
