Integrative Mapping of Regulatory Variation in African American Hepatocytes Using Colocalization and MPRA: Toward...

Genomic datasets informing pharmacogenomic discovery often underrepresent individuals of African ancestry, limiting understanding of ancestry-specific regulatory variation and its implications for precision medicine. This gap hampers accurate gene regulatory modeling and equitable delivery of precision medicine.

We generated an expression quantitative trait loci (eQTL) dataset from 75 primary human hepatocytes derived from cadaveric livers of African American (AA) donors and integrated these data with public liver eQTL resources.Cis-eQTL mapping identified 31,606 eQTLs (SNP-gene pairs), including regulatory variation in pharmacogenomic-relevant genes such as CYP4F11, SLC47A1, SLC28A1, and GSTM3. Of these, 17,585 were specific to the AA-hepatocyte dataset, including the clinically actionable gene F5, suggesting ancestry-specific regulatory mechanisms. These AA-specific eQTLs exhibited greater allele frequency differentiation than colocalized eQTL signals (mean Fst = 0.163 vs. 0.139, p < 2.2×10^-16) and lower effect size correlation (ρ = 0.314 vs. 0.619). Colocalization analysis with GTEx and Broadaway liver datasets identified shared eQTL signals with GTEx, comprising 2,658 variants within 95% credible sets, indicating shared regulatory architecture. Integration with massively parallel reporter assay (MPRA) data further supported the functional relevance of prioritized variants, including loci within GSTM3, an important drug-metabolizing enzyme.

By integrating ancestry-specific eQTL mapping, colocalization, and functional assays, this study improves the resolution of causal regulatory variants in hepatocytes. Expanding diverse population cohorts and incorporating functional assays in relevant tissue will be crucial to further disentangle the complex genetic architecture of hepatic gene regulation. Our findings expand the understanding of regulatory mechanisms underlying pharmacogenomic traits and advance precision medicine in admixed populations.