Inflammatory bowel disease comprises of Crohn's disease and ulcerative colitis, two clinical entities with overlapping but distinct patterns of recurrent gastrointestinal inflammation. Together, these diseases affect 1.4 million Americans, with typical onset in late childhood and early adulthood, and can result in morbidity extending over multiple decades. Among complex diseases, genome wide association studies (GWAS) have been particularly successful in the identification of genes for inflammatory bowel disease, with 163 confirmed gene loci to date. Identification of these loci has contributed greatly to our understanding of the pathophysiology of these diseases, with both diseases linked to genes in the IL23/Th17 T-cell pathway, as well as an exclusive Crohn's disease association to genes in the NOD2/ATG16L1 autophagy pathway. However, the success of GWAS has been tempered by the difficulty of identifying the precise DNA sequence changes that lead to disease and understanding their function. Particularly challenging is the fact that only ~12% of GWAS hits appear to nominate variants that affect amino acid sequence, and therefore most causal variants are presumably regulatory mutations that alter gene expression. This proposal aims to utilize both ultra- densely genotyped simple nucleotide polymorphism (SNP) data and novel statistical methods to determine the causal variants underlying inflammatory bowel disease. Once these are identified, we propose to investigate their association with cell-type specific enhancers, DNAse hypersensitivity sites, transcription factor and microRNA binding sites, and other regulatory interactions. By elucidating how noncoding variants produce their effects, we hope to gain a more complete understanding of the complex regulatory programs differentiating health from disease, as well as pioneering new techniques for bridging the gap between genetic association and biological processes.
This proposal seeks to identify specific noncoding variants that modulate risk for inflammatory bowel disease and to investigate their function. Recent advances, such as the Encylcopedia of DNA Elements (ENCODE) project, have shown that noncoding regions of the genome are highly active in gene regulation. Identifying disease-associated variants disrupting these functions has the potential to offer guidance for future development of therapy.
