Genome-wide association studies (GWAS) have emerged as powerful approaches for identifying genetic variants influencing common, complex diseases and traits [Hunter et al., 2007; Sladek et al., 2007; Wellcome Trust Case Control Consortium, 2007; Yeager et al., 2007]. Most genetic loci discovered to date, however, account for only a small fraction of total phenotypic variation and most of the inherited component of risk remains unexplained. Some of this missing inherited risk, i.e. that proportion not attributable to variants identified to date, might be due to gene-environment (G × E) interactions that, when present, may adversely affect the ability to uncover risk loci [McCarthy and Hirschhorn, 2008]. Nearly all GWAS to date have concentrated on detecting and characterizing main effects and have not fully explored the potential role environmental factors play in modifying genetic risk [Clayton and McKeigue, 2001; Dempfle et al., 2008; Martinez, 2008]. Whether, and to what extent, the GWAS approach can be used to uncover these potential G × E interactions remains uncertain.
