Tests for Gene-Environment Interactions and Joint Effects with Exposure Misclassification

摘要

The number of methods for genome-wide testing of gene-environment interactions (GEI) continues to increase with the hope of discovering new genetic risk factors and obtaining insight into the disease-gene-environment relationship. The relative performance of these methods based on family-wise type 1 error rate and power depends on underlying disease-gene-environment associations, estimates of which may be biased in the presence of exposure misclassification. This simulation study expands on a previously published simulation study of methods for detecting GEI by evaluating the impact of exposure misclassification. We consider seven single step and modular screening methods for identifying GEI at a genome-wide level and seven joint tests for genetic association and GEI, for which the goal is to discover new genetic susceptibility loci by leveraging GEI when present. In terms of statistical power, modular methods that screen based on the marginal disease-gene relationship are more robust to exposure misclassification. Joints tests that include main/marginal effects of a gene display a similar robustness, confirming results from earlier studies. Our results offer an increased understanding of the strengths and limitations of methods for genome-wide search for GEI and joint tests in presence of exposure misclassification. KEY WORDS: case-control; genome-wide association; gene discovery, gene-environment independence; modular methods; multiple testing; screening test; weighted hypothesis test. Abbreviations: CC, case-control; CC(EXP), CC in the exposed subgroup; CO, case-only; CT, cocktail; DF, degree of freedom; D-G, disease-gene; EB, empirical Bayes; EB(EXP), EB in the exposed subgroup; EDGxE, joint marginal/association screening; FWER, family-wise error rate; G-E, gene-environment; GEI, gene-environment interaction; GEWIS, Gene Environment Wide Interaction Study; H2, hybrid two-step; LR, likelihood ratio; MA, marginal; OR, odds ratio; SE, sensitivity; SP, specificity; TS, two-step gene-environment screening;