Genetic variants can affect qualitative and quantitative aspects at all levels of gene expression, including gene transcription, splicing, transcript stability, rate of translation, protein function and degradation, thereby contributing to inter-subject variability and heritable metabolic, pharmacogenetic and other phenotypes. Many variants, in particular, common single-nucleotide polymorphisms (SNPs), affect gene expression in a quantitative manner, and the combination of larger sets of low-impact variants is believed to explain non-Mendelian types of inheritance, including complex quantitative traits such as body size.1, 2, 3 Typical pharmacological phenotypes, such as drug response and toxicity, are highly likely to depend on multiple genes. In contrast to monogenically inherited pharmacogenetic polymorphisms, most of which have been discovered by following up on unusual clinical drug response phenotypes,4 the basis for more complex phenotypes remained largely unknown.5, 6
