Twin studies and familial clustering of the idiopathic inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), provide strong evidence that IBD is a heritable trait with complex genetics. The investigators' preliminary data show that they have replicated linkage between IBD and the chromosome 12q13-14, IBD2 locus that was originally detected in a genome scan performed in the United Kingdom. They have also shown that most of the evidence for linkage to IBD2 comes from UC families, and that there is significant linkage heterogeneity between UC and CD at IBD2, which might, in part, explain the failure to observe linkage to IBD2 in some CD-dominated datasets. The investigators have found significant departure from random allele transmission to familial UC-affected individuals at a microsatellite that is located within the IBD2 linkage interval. Sequence analysis of two nearby candidate genes does not reveal coding region sequence variations that are likely to explain the linkage evidence. The investigators now propose to participate in the Inflammatory Bowel Disease Genetics Research Consortium as a Genetics Research Center, and they propose that fine mapping the IBD2 locus is a worthy project for the consortium to facilitate. The investigators propose to carry out a linkage disequilibrium mapping exercise across a three megabase region centered on the microsatellite that shows significant departure from random allele transmission to familial UC-affected individuals. The study sample will be limited to independent nuclear families with at least one UC-affected offspring, a family history of UC in another relative, and one or two unaffected parents. The investigators will develop a 20 kilobase grid of single nucleotide polymorphism (SNP) markers across the three megabase region, genotype the SNP markers in 576 members of independent nuclear families that meet the inclusion criteria, and use a variety of methods to analyze the patterns of linkage disequilibrium. Since the investigators will have at their disposal families, rather than examining single markers one at a time, they will use more powerful haplotype-based approaches to identify the interval that is most likely to contain the UC-predisposing genetic variant. The investigators will also recruit and phenotype study subjects for Inflammatory Bowel Disease Genetics Research Consortium projects.
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