Local Ancestry-Informed Candidate Pathway Analysis of Warfarin Stable Dose in Latino Populations

Accuracy of warfarin dose prediction algorithms may be improved by including data from diverse populations in genetic studies of dose variability. Here, we surveyed single nucleotide polymorphisms in vitamin K-related genetic pathways for association with warfarin dose requirements in two admixed Latino populations in standard-principal component adjusted and contemporary-local ancestry adjusted regression models. A total of five variants from vitamin K-related genes/pathways were associated with warfarin dose in both cohorts (P < 0.0125) in standard models. Local ancestry-adjusted analysis unveiled 35 associated variants with absolute effects ranging from beta = 9.04 ( +/-;2.23) to 39.18 (+/- 10.89) per ancestral allele in the discovery cohort and beta = 6.47 (+/- 2.02) to 17.82 (+/- 6.83) in the replication cohort. Importantly, we demonstrate the technical validity of the Tractor model in cohorts with admixed ancestry from three founder populations and bring attention to the technical hurdles obstructing the inclusion of diverse, especially admixed, populations in pharmacogenomic research.

Automated summary

The accuracy of warfarin dose prediction algorithms can be improved by including data from diverse populations in genetic studies, as demonstrated by this study. It also highlights the technical challenges of including diverse, especially admixed populations in pharmacogenomic research.