Fine-mapping variants and genes that contribute to celiac disease

Complex diseases like type-1 diabetes, multiple sclerosis, and celiac disease (CeD) are difficult to unravel from a genetic perspective because they are caused by many mutations (DNA variants) that can be present in many different combinations. This is further complicated by the fact that over 95% of these variants are located in non-coding DNA, making it difficult to identify which genes they affect. Hence, in this thesis we applied cutting-edge, high-throughput fine-mapping methods to identify the variants, genes, non-coding regulatory elements, and cell states that contribute to CeD. We developed the high-throughput method Survey of Regulatory Elements and SNPs (SuRE-SNP) that tests over 400 million plasmids (small circular DNA of interest) in multiple CeD-associated cell-types to identify which non-coding CeD-associated locations and variants have gene regulatory potential. SuRE-SNP identified hundreds of non-coding regulatory elements in epithelial cells, of which three contain CeD-associated variants that we validated to strongly alter their regulatory potential. In a second fine-mapping project, we explored the binding of STAT proteins to DNA in CD8+ intraepithelial lymphocytes (IELs) under CeD-specific stimulations. We identified a possible central regulatory role for STATs in CD8+ IELs during CeD-specific stimulations. Moreover, we identified a possible role for T-cell stimulation in cytotoxic activation of CD8+ IELs. A total of 73 CeD-associated genes that are regulated by STATs and play a role in the activation of CD8+ IELs were prioritized, including the RGS1 gene whose gene expression can be disrupted by a STAT-binding CeD-associated variant.