Local ancestry informed GWAS of warfarin dose requirement in African Americans identifies a novel CYP2C19 splice QTL

Abstract

African Americans (AAs) are underrepresented in pharmacogenomics which has led to a significant gap in knowledge. AAs are admixed and can inherit specific loci from either their African or European ancestor, known as local ancestry (LA). A previous study in AAs identified single nucleotide polymorphisms (SNPs) located in the CYP2C cluster that are associated with warfarin dose. However, LA was not considered in this study. An IWPC cohort (N=340) was used to determine the LA-adjusted association with warfarin dose. Ancestry-specific GWASs were conducted with TRACTOR and ancestry tracts were meta-analyzed using METAL. We replicated top associations in the independent ACCOuNT cohort of AAs (N=309) and validated associations in a warfarin pharmacokinetic study in AAs. To elucidate functional roles of top associations, we performed short-read RNA-sequencing from AA hepatocytes carrying each genotype for expression of CYP2C9 and CYP2C19. We identified 6 novel 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 including rs7906871, previously associated SNPs, clinical and demographic factors explain 37% of dose variability, greater than previously reported studies in AAs. RNA-seq data in AA hepatocytes 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 novel CYP2C variant associated with warfarin dose requirement and potential functional consequences to CYP2C19.