Statistical Genetic Analysis of Orofacial Cleft Families

描述（由申请人提供）：非综合征性唇裂伴或不伴腭裂（CUP）是一种病因复杂的疾病。尽管已经做了大量的工作，有许多重要的发现，但人们对CUP的遗传学知之甚少。在这里，我们提出了一套新的分析计划，对空前规模的CUP谱系样本和1000个CUP三重奏的独立集进行分析。重要的是，该数据集具有CIDR基因组扫描数据，已被Illumina与CIDR的精细定位项目所接受，并且已经有许多候选基因座进行了基因分型。我们的分析计划将包括三种不同的方法来发现CUP基因。首先，我们将使用非参数链接方法来检测基因-基因相互作用，在模型中结合先前的链接发现或候选基因标记。其次，我们将使用关联方法来检测一组候选基因的相互作用。最后，我们将使用经验信息来告知一种新的方法，以结合一个参数代表诊断不确定性的联系分析。总的来说，在这个大型数据集中应用的建议分析方法将对特定基因及其相互作用对CUP的贡献有重要的启示。

DESCRIPTION (provided by applicant): Nonsyndromic cleft lip with or without cleft palate (CUP) is a disease of complex etiology. Although significant work has been done, with many important findings, the genetics of CUP is poorly understood. Herein we present a plan for a novel set of analyses on a CUP pedigree sample of unprecedented size and an independent set of 1000 CUP trios. Importantly, this dataset has CIDR genome scan data available, has been accepted for an Illumina fine-mapping project with CIDR and has many candidate loci already genotyped. Our analysis plan will consist of three distinct approaches to CUP gene discovery. First, we will use a non-parametric linkage approaches to detecting gene-gene interaction, incorporating either a previous linkage finding or candidate gene marker in the model. Second, we will use association approaches to detect interaction at a set of candidate genes. Lastly, we will use empirical information to inform a novel approach to linkage analysis incorporating a parameter representing diagnostic uncertainty. Overall, the proposed analytical approaches applied in this large dataset will shed significant light on the contribution of specific genes, and their interactions, to CUP.