© 2014 by The American Society of Hematology. The anticoagulant warfarin has < 30 million prescriptions per year in the United States. Doses can vary 20-fold between patients, and incorrect dosing can result in serious adverse events. Variation in warfarin pharmacokinetic and pharmacodynamic genes, suchasCYP2C9andVKORC1,donot fully explainthedosevariability inAfricanAmericans. To identify additional genetic contributors to warfarin dose, we exome sequenced 103 African Americans on stable doses of warfarin at extremes (≥35 and (≤49 mg/week). We found an association between lowerwarfarin dose and a population-specific regulatory variant, rs7856096 (P = 1.82 × 10-8, minor allele frequency =20.4%), in the folate homeostasis gene folylpolyglutamate synthase (FPGS). We replicated this association in an independent cohort of 372 African American subjects whose stable warfarin doses represented the full dosing spectrum (P =.046). In a combined cohort, adding rs7856096 to the International Warfarin Pharmacogenetic Consortium pharmacogenetic dosing algorithm resulted in a 5.8 mg/week (P=3.93 × 10-5) decrease in warfarin dose for each allele carried. The variant overlaps functional elements and was associated (P =.01) with FPGS gene expression in lymphoblastoid cell lines derived from combined HapMap African populations (N =326). Our results provide the first evidence linking genetic variation in folatehomeostasis to warfarin response.