Practice of Epidemiology Simultaneously Testing for Marginal Genetic Association and Gene- Environment Interaction

In this article, the authors propose to simultaneously test for marginal genetic association and gene-environment interaction to discover single nucleotide polymorphisms that may be involved in gene-environment or genetreatment interaction. The asymptotic independence of the marginal association estimator and various interaction estimators leads to a simple and flexible way of combining the 2 tests, allowing for exploitation of geneenvironment independence in estimating gene-environment interaction. The proposed test differs from the 2-df test proposed by Kraft et al. (Hum Hered. 2007;63(2):111–119) in two respects. First, for the genetic association component, it tests for marginal association, which is often the primary objective in inference, rather than the main effect in a model with gene-environment interaction. Second, the gene-environment testing component can easily exploit putative gene-environment independence using either the case-only estimator or the empirical Bayes estimator, depending on whether the goal is gene-treatment interaction in a randomized trial or geneenvironment interaction in an observational study. The use of the proposed joint test is illustrated through simulations and a genetic study (1993–2005) from the Women’s Health Initiative.