Leveraging drug perturbation to reveal genetic regulators of hepatic gene expression in African Americans

Abstract

Expression quantitative locus (eQTL) studies have paved the way in identifying genetic variation impacting gene expression levels. African Americans (AAs) are disproportionately underrepresented in eQTL studies, resulting in a lack of power to identify population-specific regulatory variants especially related to drug response. Specific drugs are known to affect the biosynthesis of drug metabolism enzymes as well as other genes. We used drug perturbation in cultured primary hepatocytes derived from AAs to determine the effect of drug treatment on eQTL mapping and to identify the drug response eQTLs (reQTLs) that show altered effect size following drug treatment. Whole-genome genotyping (Illumina MEGA array) and RNA sequencing were performed on 60 primary hepatocyte cultures after treatment with six drugs (Rifampin, Phenytoin, Carbamazepine, Dexamethasone, Phenobarbital, and Omeprazole) and at baseline (no treatment). eQTLs were mapped by treatment and jointly with Meta-Tissue. We found varying transcriptional changes across different drug treatments and identified Nrf2 as a potential general transcriptional regulator. We jointly mapped eQTLs with gene expression data across all drug treatments and baseline, which increased our power to detect eQTLs by 2.7-fold. We also identified 2,988 reQTLs (eQTLs with altered effect size after drug treatment). reQTLs were more likely to overlap transcription factor binding sites, and we uncovered reQTLs for drug metabolizing genes such as CYP3A5. Our results provide insights into the genetic regulation of gene expression in hepatocytes through drug perturbation and provide insight into SNPs that effect the liver's ability to respond to transcription upregulation.