The case-only test for gene-environment interaction is not uniformly powerful: an empirical example

The case-only test has been proposed as a more powerful approach to detect gene-environment (G × E) interactions. This approach assumes that the genetic and environmental factors are independent. Although it is well known that Type I error rate will increase if this assumption is violated, it is less widely appreciated that G × E correlation can also lead to power loss. We illustrate this phenomenon by comparing the performance of the case-only test to other approaches to detect G × E interactions in a genome-wide association study (GWAS) of esophageal squamous-cell carcinoma (ESCC) in Chinese populations. Some of these approaches do not use information on the correlation between exposure and genotype (standard logistic regression), whereas others seek to use this information in a robust fashion to boost power without increasing Type I error (two-step, empirical Bayes, and cocktail methods). G × E interactions were identified involving drinking status and two regions containing genes in the alcohol metabolism pathway, 4q23 and 12q24. Although the case-only test yielded the most significant tests of G × E interaction in the 4q23 region, the case-only test failed to identify significant interactions in the 12q24 region which were readily identified using other approaches. The low power of the case-only test in the 12q24 region is likely due to the strong inverse association between the single nucleotide polymorphism (SNPs) in this region and drinking status. This example underscores the need to consider multiple approaches to detect G × E interactions, as different tests are more or less sensitive to different alternative hypotheses and violations of the G × E independence assumption.