MOLECULAR QTLS IN DISEASED TISSUE REVEAL GENETIC MECHANISMS OF INFLAMMATORY BOWEL DISEASE

The Inflammatory bowel diseases (IBDs), Crohn’s disease and ulcerative colitis are chronic inflammatory disorders that cause damage to the gastrointestinal tract. There is no cure for IBD. Current therapies treat inflammatory responses but do not target underlying causes. Research improving our understanding of underlying causes of IBD can lead to improved treatment of disease. While over 300 genomic loci have been associated with IBD by genome-wide association studies (GWAS), only a handful of these loci have known molecular mechanisms. Loci falling within non-coding regions suggests variants perturb regulatory mechanisms by altering transcription factor binding and local chromatin structure but identifying exact mechanisms and target genes remains challenging using GWAS alone. Mapping molecular quantitative trait loci associate traits such as gene expression (eQTL) and chromatin accessibility (caQTL) with genetic variants, provides evidence to functionally link variants to regulatory mechanisms and target genes. Furthermore, I hypothesize that mapping QTL in diseased tissue specifically will identify regulatory mechanisms active in disease. In the following chapters I show that mapping eQTL in IBD tissue uncovers novel potential target genes associated with IBD whose genetic signals in non-IBD tissue did not colocalize with GWAS. Additionally, I have performed the first caQTL mapping in colon tissue using both IBD and non-IBD samples. Combining these data sets together I have generated mechanistic hypotheses for regulatory variants associated with IBD including identifying regulatory variants, their predicted effects on chromatin accessibility and transcription factor (TF) binding, and their candidate target genes. Together, the results presented here provide novel insights into the functional role of variants contributing to the molecular pathogenesis of IBD that can be used to guide future functional validation studies.