Discovery and Functional Validation of Hepatic eQTLs

About This Grant

Project Summary Currently, many genome-wide association studies (GWAS) show that single nucleotide polymorphisms (SNPs) associated with drug response and drug metabolism are in non-coding regions of the genome, requiring multi- omic data to better ascertain function. Multi-omic data exist for populations of European ancestry and have been used extensively to elucidate the target genes of associated SNPs through studies of expression quantitative trait loci (eQTLs). However, population diversity within publicly available multi-omic databases is sorely lacking, limiting the ability to utilize the greater diversity in African Ancestry populations to enable discovery for all populations. Our work will fill this gap. We plan to 1) Identify regulatory variants affecting drug-metabolizing enzymes using multi-omics data gathered in hepatocytes, 2) Determine the function of eQTLs via a massively parallel reporter assay in HepG2 and 3) Investigate the effect of eQTLs on the enzyme activity of drug- metabolizing enzymes via prime editing. The need for more predictive biomarkers is clear, and our work will fill this gap.