DETECTING PARENT-OF-ORIGIN EFFECTS FROM PEDIGREE DATA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 人类中的父母起源现象现在已经被很好地认识到，印记基因的放松管制已经与许多人类疾病有关。最近，已经开发了几种连锁分析方法，以在家系数据分析中考虑到父母的起源效应。然而，一般来说，人们不知道是否有致病基因的印记。如果没有压印，允许压印的链接方法可能会失去动力。相反，如果由于未正确指定外显率值而存在印记，则不允许印记的链接方法将失去动力。因此，在进行连锁分析之前，了解印记是否是疾病遗传的一种可能模式是很重要的。在这篇文章中，我们描述了一种简单的协变量编码方案来检验亲本起源效应的存在，并提供了在任何连锁分析之前计算亲本特定外显值的公式。在模拟研究中，我们的编码方案成功地检测到了起源父母效应，并且，当按顺序或通过单个先证者确定家系时，包括该协变量比不包括这样的协变量时更准确地估计了外显值。当疾病轨迹被印记时，在允许印记的连锁分析中使用准确的外显值可以提供更高的功率。最后，我们将我们的方法应用于27个Beckwith-Wiedemann综合征(BWS)家系，发现基于似然比检验的母系表达的亲本模型是最简约的，这表明父系印记基因在BWS中起到了作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The parent-of-origin phenomenon in humans is now well recognized, and the deregulation of imprinted genes has been implicated in a number of human diseases. Recently, several linkage analysis methods have been developed to allow for parent-of-origin effects in the analysis of pedigree data. However, in general, one does not know a priori if disease-causing loci are imprinted or not. Linkage methods that allow for imprinting can lose power if there is no imprinting. Conversely, linkage methods that do not allow for imprinting will lose power if there is imprinting because of penetrance values not being correctly specified. Therefore, it is important to know whether imprinting is a possible mode of disease inheritance before performing linkage analyses. In this paper, we describe a simple covariate-coding scheme to test for the presence of parent-of-origin effects and provide a formula for calculating parent-specific penetrance values prior to any linkage analysis. In simulation studies, our coding scheme successfully detected parent-of-origin effects and, when pedigrees were ascertained sequentially or through a single proband, inclusion of this covariate more accurately estimated penetrance values than when such a covariate was not included. The use of accurate penetrance values in a linkage analysis that allows for imprinting can provide higher power when the disease locus is imprinted. Finally, we applied our approach to 27 Beckwith-Wiedemann syndrome (BWS) pedigrees, an overgrowth syndrome, and found that a maternally expressed parent-of-origin model based on the likelihood ratio test is the most parsimonious, suggesting a role for paternally imprinted genes in BWS.