Measuring Pharmacogene Variant Function at Scale Using Multiplexed Assays

Abstract

As costs of next-generation sequencing decrease, identification of genetic variants has far outpaced our ability to understand their functional consequences. This lack of understanding is a central challenge to a key promise of pharmacogenomics: using genetic information to guide drug selection and dosing. Recently developed multiplexed assays of variant effect enable experimental measurement of the function of thousands of variants simultaneously. Here, we describe multiplexed assays that have been performed on nearly 25,000 variants in eight key pharmacogenes (<i>ADRB2</i>, <i>CYP2C9</i>, <i>CYP2C19</i>, <i>NUDT15</i>, <i>SLCO1B1</i>, <i>TMPT</i>, <i>VKORC1</i>, and the <i>LDLR</i> promoter), discuss advances in experimental design, and explore key challenges that must be overcome to maximize the utility of multiplexed functional data.