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

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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 .