The overall goal of this application is to discover genetic risk loci for ulcerative colitis by attempting to replicate/extend the evidence for association at single nucleotide polymorphisms (SNPs) identified in a metaanalysis of ulcerative colitis genome-wide association studies (GWAS). Ulcerative colitis and Crohn's disease are the two major forms of inflammatory bowel disease. They are thought to result from a dysregulated mucosal immune response triggered by ubiquitous enteric bacteria in genetically susceptible individuals. The two disorders share many characteristics but unique clinical features also distinguish them, suggesting that they share some genetic susceptibility loci but differ at others. Genome-wide significant evidence for 32 Crohn's disease loci was found in a GWAS meta-analysis and replication study. Variants in IL23R and the major histocompatibility complex are associated with both ulcerative colitis and Crohn's disease, but most of the identified Crohn's disease loci show only nominal or no significant evidence for association with ulcerative colitis. The NIDDK Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC) recently completed an ulcerative colitis GWAS using Illumina genotyping beadchip data from 977 cases and 2,122 controls that passed quality control and were matched, by gender and ancestry. The NIDDK IBDGC's ulcerative colitis GWAS and a limited replication study in additional case-control samples, all of European ancestry, identified ulcerative colitis loci on chromosomes 1p36 and 12q15, in addition to IL23R and the major histocompatibility complex. A meta-analysis of the NIDDK IBDGC and two additional ulcerative colitis GWAS datasets, all generated in European ancestry case-control samples using Illumina genotyping beadchips, is underway. The ulcerative colitis GWAS meta-analysis is expected to include post quality control data for approximately 280,000 SNPs in more than 2,600 cases and approximately twice this number of controls. This grant application proposes to attempt to replicate/extend the most promising ulcerative colitis GWAS meta-analysis association signals in additional European ancestry case-control samples from North America, the Netherlands, Germany, Austria and Italy. In addition to genotyping the replication samples at SNPs with promising association evidence in the ulcerative colitis GWAS meta-analysis, ancestry informative markers will also be genotyped so that association analyses can be controlled for population structure. Genotyping technologies and costs are constantly evolving, so it is difficult to predict which genotyping platform will be most cost-effective, how many replication samples can be genotyped, how deep into the ulcerative colitis GWAS meta-analysis hit list the replication analyses can go, and how many ancestry informative markers can be genotyped within budget limitations at the time the proposed study would commence. The tentative plan is to use a 768-plex Illumina GoldenGate assay to genotype more than 500 of the top ulcerative colitis metaanalysis hits plus a set of SNPs that discern ancestry strata within European ancestry samples.
The discovery of genetic susceptibility loci for ulcerative colitis may lead to a better understanding of pathogenesis, development of better therapies, and improved genetic counseling. There is evidence that clinically diverse chronic, immune-mediated disorders can share genetic susceptibility loci (i.e., IL23R variants are associated with Crohn's disease, ulcerative colitis, psoriasis, ankylosing spondylitis, and Grave's ophthalmopathy), so identification of ulcerative colitis loci may also have relevance for other disorders. )
Showing the most recent 10 out of 12 publications
