Durner M, Greenberg D A, Hodge S E
Department of Psychiatry, Mount Sinai Medical Center, New York, NY 10029, USA.
Hum Hered. 1996 Sep-Oct;46(5):265-73. doi: 10.1159/000154363.
In this study we explore whether a phenocopy frequency (defined as a "penetrance' for nondisease genotypes) can approximate or model genetic heterogeneity in a single-locus analysis. We simulated two types of heterogeneity situations: "sporadic models', where there are two forms of a disease, one genetic and linked to a marker and the other purely random, and "genetic heterogeneity models', where the disease is caused by either of two different loci, one linked to the marker and the other unlinked. We analyzed simulated data sets for linkage, assuming a single-locus analysis with varying phenocopy frequency, in analogy with earlier work on epistatic two-locus models. We found that in the presence of purely random sporadics, there was a difference between assuming any nonzero phenocopy frequency and a zero frequency, but that the actual value of the assumed phenocopy frequency had little effect on the maximum lod score. In contrast, when both forms of disease are genetic, and are generated under similar genetic parameters, assuming a positive phenocopy frequency will not, in general, compensate for the presence of the unlinked form. However, when the modes of inheritance of the two forms differ, the assumption of a nonzero phenocopy frequency does have an effect, either to increase or decrease the maximum lod score, depending on the modes of inheritance of the two disease forms. We conclude with practical recommendations for investigators, based on these results.
在本研究中，我们探讨了拟表型频率（定义为非疾病基因型的“外显率”）是否能够在单基因座分析中近似或模拟遗传异质性。我们模拟了两种类型的异质性情况：“散发病例模型”，其中疾病有两种形式，一种是遗传性的且与一个标记相关联，另一种是纯粹随机的；以及“遗传异质性模型”，其中疾病由两个不同基因座中的任何一个引起，一个与标记相关联，另一个不相关联。我们分析了模拟的连锁数据集，假设进行单基因座分析并采用不同的拟表型频率，这类似于早期关于上位性双基因座模型的研究。我们发现，在存在纯粹随机散发病例的情况下，假设任何非零拟表型频率与零频率之间存在差异，但假设的拟表型频率的实际值对最大对数优势分数影响不大。相比之下，当两种疾病形式都是遗传性的，并且在相似的遗传参数下产生时，一般来说，假设正的拟表型频率并不能弥补未连锁形式的存在。然而，当两种形式的遗传方式不同时，假设非零拟表型频率确实会产生影响，根据两种疾病形式的遗传方式，要么增加要么降低最大对数优势分数。基于这些结果，我们为研究人员给出了实际建议。
