A Comparison of Sample Size and Power in Case-Only Association Studies of Gene-Environment Interaction

摘要

Assuming continuous, normally distributed environmental and categorical genotype variables, the authors comparen6 case-only designs for tests of association in gene-environment interaction. Novel tests modeling thenenvironmental variable as either the response or the predictor and allowing a genetic variable with multiallelicnvariants are included. The authors show that tests imposing the same genotypic pattern of inheritance performnsimilarly regardless of whether genotype is the response variable or the predictor variable. The novel tests usingnthe genetic variable as the response variable are advantageous because they are robust to non-normally distributednenvironmental exposures. Dominance deviance—deviation from additivity in the main or interaction effects—nis key to test performance: When it is zero or modest, tests searching for a trend with increasing risk alleles arenoptimal; when it is large, tests for genotypic effects are optimal. However, the authors show that dominancendeviance is attenuated when it is observed at a proxy locus, which is common in genome-wide association studies,nso large dominance deviance is likely to be rare. The authors conclude that the trend test is the appropriate tool fornlarge-scale association scans where the true gene-environment interaction model is unknown. The commonnpractice of assuming a dominant pattern of inheritance can cause serious losses of power in the presence ofnany recessive, or modest dominant, effects.