Uncovering the role of admixture in disease and drug response: Association of hepatocyte gene expression and DNA methylation with African Ancestry in African Americans

Abstract

ABSTRACTBackgroundAfrican Americans (AAs) are an admixed population with portions of their genome derived from West Africans and Europeans. In AAs, the proportion of West African ancestry (WAA) can vary widely and may explain the genetic drivers of disease, specifically those that disproportionately affect this understudied population. To examine the relationship between the proportion of WAA and gene expression, we used high dimensional data obtained from AA primary hepatocytes, a tissue important in disease and drug response.MethodsRNA sequencing (Illumina HiSeq Platform) was conducted on 60 AA-derived primary hepatocytes, with methylation profiling (Illumina MethylationEPIC BeadChip) of 44 overlapping samples. WAA for each sample was calculated using fastSTRUCTURE and correlated to both gene expression and DNA methylation. The GTEx consortium (n = 15) was used for replication and a second cohort (n = 206) was using used for validation using differential gene expression between AAs and European-Americans.ResultsWe identified 131 genes associated with WAA (FDR< 0.1), of which 28 gene expression traits were replicated (FDR<0.1) and enriched in angiogenesis and inflammatory pathways (FDR<0.1). These 28 replicated gene expression traits represented 257 GWAS catalog phenotypes. Among the PharmGKB pharmacogenes, VDR, PTGIS, ALDH1A1, CYP2C19 and P2RY1 were associated with WAA (p < 0.05) with replication of CYP2C19 and VDR in GTEx. Association of DNA methylation with WAA identified 1037 differentially methylated regions (FDR<0.05), with hypomethylated genes enriched in drug response pathways. Overlapping of differentially methylated regions with the 131 significantly correlated gene expression traits identified 5 genes with concordant directions of effect: COL26A1, HIC1, MKNK2, RNF135, SNAI1 and TRIM39.ConclusionsWe conclude that WAA contributes to variability in hepatic gene expression and DNA methylation with identified genes indicative of diseases disproportionately affecting AAs. Specifically, WAA-associated genes were linked to previously identified loci in cardiovascular disease (PTGIS, PLAT), renal disease (APOL1) and drug response (CYP2C19).