Global patterns of genetic diversity and signals of natural selection for human ADME genes

Abstract

Genetic polymorphisms in many genes related to drug absorption, distribution, metabolism and excretion (ADME genes) contribute to the high heterogeneity of drug responses in humans. However, the extent to which genetic variation in ADME genes may contribute to differences among human populations in drug responses has not been studied. In this work, we investigate the global distribution of genetic diversity for 31 core and 252 extended ADME genes. We find that many important ADME genes are highly differentiated across continental regions. Additionally, we analyze the genetic differentiation associated with clinically relevant, functional polymorphism alleles, which is important for evaluating potential among-population heterogeneity in drug treatment effects. We find that ADME genes show significantly greater variation in levels of population differentiation, and we find numerous signals of recent positive selection on ADME genes. These results suggest that genetic differentiation at ADME genes could contribute to population heterogeneity in drug responses.