title: Gene-environment interactions in genome-wide association studies: a comparative study of tests applied to empirical studies of type 2 diabetes.
abstract: The question of which statistical approach is the most effective for investigating gene-environment (G-E) interactions in the context of genome-wide association studies (GWAS) remains unresolved. By using 2 case-control GWAS (the Nurses' Health Study, 1976-2006, and the Health Professionals Follow-up Study, 1986-2006) of type 2 diabetes, the authors compared 5 tests for interactions: standard logistic regression-based case-control; case-only; semiparametric maximum-likelihood estimation of an empirical-Bayes shrinkage estimator; and 2-stage tests. The authors also compared 2 joint tests of genetic main effects and G-E interaction. Elevated body mass index was the exposure of interest and was modeled as a binary trait to avoid an inflated type I error rate that the authors observed when the main effect of continuous body mass index was misspecified. Although both the case-only and the semiparametric maximum-likelihood estimation approaches assume that the tested markers are independent of exposure in the general population, the authors did not observe any evidence of inflated type I error for these tests in their studies with 2,199 cases and 3,044 controls. Both joint tests detected markers with known marginal effects. Loci with the most significant G-E interactions using the standard, empirical-Bayes, and 2-stage tests were strongly correlated with the exposure among controls. Study findings suggest that methods exploiting G-E independence can be efficient and valid options for investigating G-E interactions in GWAS.
authors.affiliation: Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. mcorneli@hsph.harvard.edu
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Cornelis
authors.forename: Eric J Tchetgen
authors.initials: EJ
authors.lastname: Tchetgen
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.forename: Lu
authors.initials: L
authors.lastname: Qi
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
authors.forename: Frank B
authors.initials: FB
authors.lastname: Hu
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
mesh_terms: D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D008297:Male