(Georgia Institute of Technology, 2024-04-26)
Brown, Margaret R.
In the post-GWAS era, genetic associations with pathology have sparked interest in gene regulatory mechanisms since the majority of GWAS variants are located in noncoding regions. This idea fuels the hypothesis that trait associated variants are causal to gene expression variability. The primary question driving this thesis, is whether distinct gene regulatory mechanisms associated with genetics can be identified in circulating immune cells. First, eQTL fine mapping was performed using an all-but-one conditional analysis approach to prioritize putatively causal variants by disentangling the effects of linkage disequilibrium in peripheral blood. Identified eQTL for genes associated with inflammatory bowel disease were observed in immune cell populations, suggesting a functional relationship between genetics and gene expression variability. Next, heterogeneous gene regulatory mechanisms were observed in single nuclear multiomic data of circulating immune cells from individuals with Crohn’s disease and healthy donors. Paralleled heterogeneity was observed in both arms of the adaptative immune system, including an inflammatory signature within a subset of Crohn’s disease donors. Finally, an unprecedented approach to explain gene expression was implemented by training machine learning models on chromatin accessibility data, which demonstrated that ATAC peaks which are important for explaining gene expression are enriched with inflammatory disease GWAS variants. Altogether, this thesis highlights the genetic relevance of gene regulation in circulating immune cells for inflammatory disease and suggests that the interplay of genetics and pathology with respect to gene regulation is complex and heterogeneous among individuals.