Bayesian Reanalysis of a Multi-Site Gene-Mapping Study of Cleft Lip/Cleft Palate

描述(申请人提供)：本申请是对PAR-04-091的回应。该项目的目标是将新的数据分析方法应用于现有的数据集，以便定位所有与非综合征性唇裂(COP)相关的可测量的影响基因。CUP是一种主要的结构性出生缺陷，代表着重大的公共卫生负担。虽然基因在病因学中的作用是确定的，但全基因组的关联研究一直没有定论。为了实现对人类CUP遗传学的全面概述，我们进行了迄今为止最大的基因图谱研究，汇集了来自世界各地7个群体的多组独立收集的显示CUP的家族。遗传病研究中心已经完成了对所有家庭的(大约)10 cM基因组筛查的基因分型，目前正在完成基于定制的1500个SNP面板的基因分型。我们现在建议使用一种新的贝叶斯方法来分析这些数据，该方法用于连锁和连锁不平衡作图，专门为基于多个遗传多样性样本的异质性疾病分析而设计。我们还将对贝叶斯方法与其他常用统计方法的性能进行系统的比较。因此，该项目将从基因组和地理两方面对CUP的遗传结构进行全面评估。它还将产生一套关于基于多地点设计的复杂疾病基因图谱研究的最佳数据分析方法的建议。

DESCRIPTION (provided by applicant): This application is in response to PAR-04-091. This goal of the project is to apply novel data analytic methods to an existing data set, in order to localize all genes of measurable effect underlying nonsyndromic cleft lip with or without cleft palate (CUP). CUP is a major structural birth defect, representing a significant public health burden. While a genetic role in etiology is certain, genome-wide linkage studies have been inconclusive. In an effort to achieve a comprehensive overview of the genetics of human CUP, we have undertaken the largest gene-mapping study to date by pooling together multiple independently collected sets of families manifesting CUP, drawn from 7 populations around the world. The Center for Inherited Disease Research has completed genotyping for an (approximate) 10 cM genome-screen on all families, and is currently completing genotyping based on a custom 1500 SNP panel. We now propose to analyze these data using a novel Bayesian approach to linkage and linkage disequilibrium mapping, specifically designed for the analysis of heterogeneous conditions based on multiple, genetically diverse samples. We will also conduct systematic comparisons of the performance of the Bayesian method with other commonly used statistics. This project will thus provide a comprehensive assessment, in both genomic and geographical terms, of the genetic architecture of CUP. It will also result in a set of recommendations regarding optimal data analytic methods for gene mapping studies of complex disorders based on multi-site designs .