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

描述（由申请人提供）：此申请是对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，以便定位所有可测量影响非综合征性唇裂伴或不伴腭裂（CUP）的基因。CUP是一种主要的结构性出生缺陷，对公共卫生造成重大负担。虽然遗传在病因学中的作用是确定的，但全基因组连锁研究尚无定论。为了全面了解人类CUP的遗传学，我们进行了迄今为止最大规模的基因定位研究，从世界各地的7个人群中收集了多组独立收集的CUP家族。遗传疾病研究中心已经完成了所有家庭（大约）10厘米基因组筛选的基因分型，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，这种方法专门用于分析基于多个遗传多样性样本的异质条件。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比较。因此，该项目将从基因组和地理角度对CUP的遗传结构进行全面评估。它还将产生一组关于基于多位点设计的复杂疾病基因定位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 .