Local ancestry-informed GWAS of warfarin dose requirement in African Americans identifies a CYP2C19 splicing QTL.

Abstract

African Americans (AAs) are underrepresented in pharmacogenomics research, which has led to a significant gap in knowledge. Through admixture, AAs can inherit specific loci from either their African or European ancestors, known as local ancestry (LA). A previous study in AAs identified SNPs located in the CYP2C cluster that are associated with warfarin dose. However, LA was not considered in that study. Here, we conducted an ancestry-adjusted genome-wide association study (GWAS) in the AA International Warfarin Pharmacogenomics Consortium (IWPC) cohort (n = 340). We replicated top associations in the independent ACCOuNT cohort of AAs (n= 309) and validated associations in a warfarin pharmacokinetic study in AAs (n = 63). We performed RNA sequencing (RNA-seq) of AA hepatocytes carrying each genotype to assess expression and splicing of CYP2C9 and CYP2C19. We identified 6 genome-wide significant SNPs (p < 5E-8) in the CYP2C locus (lead SNP, rs7906871 [p = 3.14E-8]). These associations were replicated (p ≤ 2.76E-5) and validated with a pharmacokinetic association for S-warfarin concentration in plasma (p = 0.048). rs7906871 explains 6.0% of the variability in warfarin dose in AAs. Multivariate regression demonstrated that rs7906871 and known genetic, clinical, and demographic factors explain 37% of dose variability, greater than previously reported in AAs. RNA-seq analysis identified a significant alternate exon inclusion event between exons 6 and 7 in CYP2C19 for carriers of rs7906871. In conclusion, we have found and replicated a CYP2C variant associated with warfarin dose requirement with functional consequences to CYP2C19. CYP2C19 is involved in the metabolism of 10%-15% of commonly prescribed drugs today. This finding could have broader impacts for drug response and pharmacogenomics.