A robust identity-by-descent procedure using affected sib pairs: multipoint mapping for complex diseases.
A robust identity-by-descent procedure using affected sib pairs: multipoint mapping for complex diseases.
复制标题
DOI：
10.1159/000022961
复制
发表时间：
2001-01-01
期刊：
影响因子：
1.8
通讯作者：
Beaty, T H
中科院分区：
文献类型：
--
作者：
Liang, K Y;Chiu, Y F;Beaty, T H
多点连锁分析是定位复杂疾病易感基因的有力工具。然而，传统的lod评分方法严重依赖于遗传模式的正确规范来准确估计基因位置。另一方面，目前实践的等位基因共享方法旨在检验无连锁的零假设，而不是估计易感基因的位置。在本文中，我们提出了一种基于血统同一性（IBD）的程序来估计由多个标记构成的染色体区域内未观察到的易感基因的位置。在这里，我们处理一些实际情况，其中一些标记可能无法提供完整的信息。相反，使用多点标记信息来估算区域内任意位置的IBD统计量。该方法是稳健的，因为除了该区域包含不超过一个易感基因之外，不需要关于遗传机制的假设。特别是，该方法建立在使用受影响同胞对的数据对该区域内任何任意位点的预期 IBD 的简单表示的基础上。利用这种表示，人们可以执行参数推理程序来定位未观察到的易感基因。此外，在这里我们推导出检测与多个标记的连锁所需的受影响同胞对的数量的样本量公式。自始至终，所提出的方法都是通过模拟数据来说明的。我们已经实施了这种方法，包括探索性和正式的模型拟合程序来定位易感基因，以及程序 GENEFINDER 中的样本量和功效计算，该程序将很快推出。
Multipoint linkage analysis is a powerful tool to localize susceptibility genes for complex diseases. However, the conventional lod score method relies critically on the correct specification of mode of inheritance for accurate estimation of gene position. On the other hand, allele-sharing methods, as currently practiced, are designed to test the null hypothesis of no linkage rather than estimate the location of the susceptibility gene(s). In this paper, we propose an identity-by-descent (IBD)-based procedure to estimate the location of an unobserved susceptibility gene within a chromosomal region framed by multiple markers. Here we deal with the practical situation where some of the markers might not be fully informative. Rather the IBD statistic at an arbitrary within the region is imputed using the multipoint marker information. The method is robust in that no assumption about the genetic mechanism is required other than that the region contains no more than one susceptibility gene. In particular, this approach builds upon a simple representation for the expected IBD at any arbitrary locus within the region using data from affected sib pairs. With this representation, one can carry out a parametric inference procedure to locate an unobserved susceptibility gene. In addition, here we derive a sample size formula for the number of affected sib pairs needed to detect linkage with multiple markers. Throughout, the proposed method is illustrated through simulated data. We have implemented this method including exploratory and formal model-fitting procedures to locate susceptibility genes, plus sample size and power calculations in a program, GENEFINDER, which will be made available shortly.