Estimation and testing of gene–environment interactions in family-based association studies

Gene–environment interactions are of interest in genetic association studies for several reasons. First, the power to detect genetic effects may be substantially decreased if those effects differ according to environmental exposure and if no account is taken of this interaction with environmental exposure in the analysis. Second, such interactions may indicate a phenomenon of genuine biological interest (whereby a particular genetic effect operates only in the presence of an environmental trigger, or vice versa), understanding of which can lead us to a greater understanding of possible mechanisms and pathways in disease progression. Here I discuss the testing and estimation of gene–environment interactions via the case/pseudocontrol and related approaches. As originally proposed, the case/pseudocontrol approach applies to case/parents trios with no missing genotype data. I discuss some recent extensions that allow larger pedigree structures with some missing genotype data and present computer simulations to compare the performance of several competing approaches.