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。虽然已经做了大量的工作，有许多重要的发现，但对CUP的遗传学知之甚少。在这里，我们提出了一个新的一套分析计划，对一个前所未有的规模和一个独立的1000个CUP三人组的CUP谱系样本。重要的是，该数据集具有可用的CIDR基因组扫描数据，已被Illumina精细定位项目接受，并且具有许多已经基因分型的候选基因座。我们的分析计划将包括三种不同的CUP基因发现方法。首先，我们将使用非参数连锁方法来检测基因-基因相互作用，将先前的连锁发现或候选基因标记纳入模型中。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，通知一种新的方法，连锁分析纳入一个参数代表诊断的不确定性。总的来说，在这个大型数据集中应用的拟议分析方法将揭示特定基因及其相互作用对CUP的贡献。

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.