Whole genome sequencing identifies high-impact variants in well-known pharmacogenomic genes.

More than 1100 genetic loci have been correlated with drug response outcomes but disproportionately few have been translated into clinical practice. One explanation for the low rate of clinical implementation is that the majority of associated variants may be in linkage disequilibrium (LD) with the causal variants, which are often elusive. This study aims to identify and characterize likely causal variants within well-established pharmacogenomic genes using next-generation sequencing data from the 1000 Genomes Project. We identified 69,319 genetic variations within 160 pharmacogenomic genes, of which 8207 variants are in strong LD (r2 >0.8) with known pharmacogenomic variants. Of the latter, eight are coding or structural variants predicted to have high impact, with 19 additional missense variants that are predicted to have moderate impact. In conclusion, we identified putatively functional variants within known pharmacogenomics loci that could account for the association signals and represent the missing causative variants underlying drug response phenotypes.