False Appearance of Gene-Environment Interactions in Genetic Association Studies

Background: Under the assumption of gene-environment independence,unknown/unmeasured environmental factors, irrespective of what they may be, can notconfound the genetic effects. This has led many people to believe that genetic heterogeneity across different levels of the studied environmental exposure should only mean gene-environment interaction—even though other environmental factors are not adjusted for. Methods: In this study, the authors derive formula for bias and conduct computer simulations under the gene-environment independence assumption. They use a real data example to demonstrate the methodologies. Results: They show that apparent gene-environment interaction can and will arise, even if the gene of interest is not associated with, and is not interacting with, the environmental factor under study and any other unmeasured environmental factor. Conclusions: It is recommended to measure and control as far as possible all strong environmental factors in genetic association studies, be they independent risk factors, mediators, or confounders.