Integrating -Omics For Studying Functional Role Of Ulcerative Colitis Risk Associated Loci.

Background: Ulcerative Colitis is chronic inflammatory condition of unknown etiology. Genome Wide Association Studies have successfully identified large number of UC risk associated loci, majority of which are located in non-protein-coding DNA regions and been showed to be enriched within regulatory elements, such as enhancers. However, the function of these UC risk associated variants is still unknow. Aim: To delineate the functional role of GWAS risk associated loci in UC relevant cell types. Method: We assessed chromatin activity (ATAC seq) and transcriptional behavior (RNA seq) of primary cell types extracted from intestinal biopsies and blood from diseased and healthy participant. Next, to pinpoint the mechanistic of how UC associated loci contributes to disease risk, we intersected our disease and cell type specific differential expression and differential chromatin accessibility data with GWAS dataset. Results: Unfortunately, due to technical and financial reasons we failed to reach the target sequencing depth for both ATAC seq and RNA seq experiments. In addition, when combined with very low participant numbers, our data sets were not strong enough to reliably identify the functional role of GWAS variants. However, for practice, we proceeded with slightly simplistic proximity-based modeling and showed that intersecting the 3 -omics studies allowed us to identify 10 regions where the lowest p-value associated SNP was in proximity to differentially expressed gene and differentially accessible chromatin region. Conclusion: We were able to compare the first time the expression levels and chromatin conformation in purified immune cell populations from intestinal tissue and peripheral blood. Unfortunately, due to poor experimental design this study was markedly underpowered and any findings from RNA seq and ATAC seq experiments should be further validated before any biological conclusions are made or used for reliable prediction of functional role of UC associated risk variants.

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2019

Author dc:creator

• Ramona, Lauma

Advisors dc:contributor.advisor

• Kaser, Arthur
• Robinson, Matthew

• Ulcerative Colitis
• GWAS

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/59aa60c3-9077-4db3-9ca8-5b32c1448554/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.64576

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/317462