The impact of gene-environment dependence and misclassification in genetic association studies incorporating gene-environment interactions.
The possibility of gene-environment interaction can be exploited to identify genetic variants associated with disease using a joint test of genetic main effect and gene-environment interaction. We consider how exposure misclassification and dependence between the true exposure E and the tested genetic variant G affect this joint test in absolute terms and relative to three other tests: the marginal test (G), the standard test for multiplicative gene-environment interaction (GE), and the case-only test for interaction (GE-CO). All tests can have inflated Type I error rate when E and G are correlated in the underlying population. For the GE and G-GE tests this inflation is only noticeable when the gene-environment dependence is unusually strong; the inflation can be large for the GE-CO test even for modest correlation. The joint G-GE test has greater power than the GE test generally, and greater power than the G test when there is no genetic main effect and the measurement error is small to moderate. The joint G-GE test is an attractive test for assessing genetic association when there is limited knowledge about casual mechanisms a priori, even in the presence of misclassification in environmental exposure measurement and correlation between exposure and genetic variants.
Lindström
Sara
S
Department of Epidemiology, Harvard School of Public Health, Boston, Mass, USA. slindstr@hsph.harvard.edu
Yen
Yu-Chun
YC
Spiegelman
Donna
D
Kraft
Peter
P
D016022:Case-Control Studies; D004777:Environment; D004812:Epidemiologic Methods; D005787:Gene Frequency; D005796:Genes; D055106:Genome-Wide Association Study; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000235:genetics