Discovery of novel hepatocyte eQTLs in African Americans

African Americans (AAs) are disproportionately affected by metabolic diseases and adverse drug events, with limited publicly available genomic and transcriptomic data to advance the knowledge of the molecular underpinnings or genetic associations to these diseases or drug response phenotypes. To fill this gap, we obtained 60 primary hepatocyte cultures from AA liver donors for genome-wide mapping of expression quantitative trait loci (eQTL) using LAMatrix. We identified 277 eGenes and 19,770 eQTLs, of which 67 eGenes and 7,415 eQTLs are not observed in the Genotype-Tissue Expression Project (GTEx) liver eQTL analysis. Of the eGenes found in GTEx only 25 share the same lead eQTL. These AA-specific eQTLs are less correlated to GTEx eQTLs. in effect sizes and have larger Fst values compared to eQTLs found in both cohorts (overlapping eQTLs). We assessed the overlap between GWAS variants and their tagging variants with AA hepatocyte eQTLs and demonstrated that AA hepatocyte eQTLs can decrease the number of potential causal variants at GWAS loci. Additionally, we identified 75,002 exon QTLs of which 48.8% are not eQTLs in AA hepatocytes. Our analysis provides the first comprehensive characterization of AA hepatocyte eQTLs and highlights the unique discoveries that are made possible due to the increased genetic diversity within the African ancestry genome. Author summary Precision medicine has enabled more accurate diagnoses, treatments and outcomes with the implementation ongoing at many US hospitals. However, much of these efforts are based on genetic associations conducted in European cohorts. The discovery of disease associated genetic variants is lacking in minority populations, leading to a growing disparity in precision medicine. Our study is the first to map eQTLs in hepatocytes obtained exclusively from African Americans. The liver is a clinically relevant organ linked to many diseases, including cardiovascular and lipid traits, in addition to its importance in drug metabolism. Our analysis replicated previously identified eQTLs within the GTEx and uncovered novel regulatory variants. Many of these novel eQTLs were discovered due to the higher allele frequency of these variants in African ancestry populations, thereby demonstrating the potential increase in power with the use of African ancestry genomes. We decreased the number of potential causal variants at GWAS loci that overlap with our eQTLs. This is important as fine-mapping of causal variants has primarily relied on functional validation. Thus, narrowing the number of potential causal variants expedites this process. Lastly, we show that by identifying both population-specific and hepatocyte-specific eQTLs in African Americans, we can identify potential genes that drive disease.