The overall goal of Project 1 is to bring a quantitative trait locus (QTL) linkage approach to the problem of identification of genes predisposing to subsets of Crohn's disease (CD). This approach, which is increasingly utilized to successfully elucidate the genetic basis of a number of complex diseases preserves the power of a genome wide scan but increases the power of identifying disease genes by utilizing a more homogenous sample for analysis. This Program Project, especially the interactions between Projects 1, 2, and 3, provides unique resources and expertise in quantitative antibody phenotyping, genetic epidemiology, and molecular genotyping that maximizes the power of this approach in IBD. This project takes advantage of data that we have developed in the current cycle: that the presence of antibodies to Saccharomyces cerevisiae (ASCA) identify a more homogeneous group of CD patients, that the distribution of ASCA is familial in both affected and unaffected CD family members, that ASCA levels are highly heritable and thus is an important trait which is likely to be successfully mapped in a linkage analysis, and that in preliminary analyses the quantitative trait of ASCA is linked to at least one gene region, the major histocompatibility complex (MHC) on the short arm of chromosome 6. We thus plan to proceed in parallel with two goals, a detailed evaluation of the MHC, and a two stage, two sample genome-wide scan for quantitative ASCA levels and other CD associated antibodies.
The first Aim of this project is to identify the chromosomal regions contributing to the expression of ASCA by a 10 cM density genome-wide scan in 120 CD families (with over 1100 relative pairs) already sampled and demonstrated to have an ASCA positive proband.
The second Aim will be to fine map to 2-3cM density the regions identified in Aim 1, with the goal of identifying those regions with the best evidence for linkage.
Aim 3 will be to confirm these latter regions in a second independent sample of similar size.
In Aim 4 we will proceed to candidate gene analyses in the linked regions.
Aim 5 takes advantage of the preliminary data in the current cycle, to proceed to extremely fine mapping of genes in the MHC.
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