Many roads to a gene-environment interaction

Despite the importance of gene-environment interactions (GxEs) in improving and operationalizing genetic discovery, interpretation of any GxEs that are discovered can be surprisingly difficult. There are many potential biological and statistical explanations for a statistically significant finding and, likewise, it is not always clear what can be claimed based on a null result. A better understanding of the possible underlying mechanisms leading to a detected GxE can help investigators decide which are and which are not relevant to their hypothesis. Here, we provide a detailed explanation of five “phenomena,” or data-generating mechanisms, that can lead to nonzero interaction estimates, as well as a discussion of specific instances in which they might be relevant. We hope that, given this framework, investigators can design more targeted experiments and provide cleaner interpretations of the associated results. [Display omitted] Various data-generating mechanisms may lead to the detection of gene-environment interactions (GxE). We describe five key phenomena, both “real” and spurious, that can produce a detectable GxE and discuss how researchers may plan experiments and interpret GxE findings and their clinical relevance in light of these phenomena.