Gene–Environment Interaction: Definitions and Study Design

TLDR

Gene–environment interaction, defined as a differential effect of an exposure or genotype on disease risk, is crucial for accurately assessing genetic and environmental influences and depends on the measurement scale. This review aims to provide a clear definition of gene–environment interaction and recommend study designs for detecting it. The authors describe five biologically plausible models linking genotypes and exposures, noting that the choice of additive or multiplicative scale depends on the study’s objective and underlying pathophysiology. The models generate distinct risk predictions, with exposure classification straightforward but genotype classification more challenging, for which several alternative strategies are proposed.

Abstract

Study of gene–environment interaction is important for improving accuracy and precision in the assessment of both genetic and environmental influences. This overview presents a simple definition of gene–environment interaction and suggests study designs for detecting it. Gene–environment interaction is defined as "a different effect of an environmental exposure on disease risk in persons with different genotypes," or, alternatively, "a different effect of a genotype on disease risk in persons with different environmental exposures." Under this strictly statistical definition, the presence or absence of interaction depends upon the scale of measurement (additive or multiplicative). The decision of which scale is appropriate will be governed by many factors, including the main objective of an investigation (discovery of etiology, public health prediction, etc.) and the hypothesized pathophysiologic model. Five biologically plausible models are described for the relations between genotypes and environmental exposures, in terms of their effects on disease risk. Each of these models leads to a different set of predictions about disease risk in individuals classified by presence or absence of a high-risk genotype and environmental exposure. Classification according to the exposure is relatively easy, using conventional epidemiologic methods. Classification according to the high-risk genotype is more difficult, but several alternative strategies are suggested.