Gene-environment interactions in genome-wide association studies: a comparative study of tests applied to empirical studies of type 2 diabetes.
paper
Cited
Public
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- Authors
- Cornelis, Marilyn C; Tchetgen, Eric J Tchetgen; Liang, Liming; Qi, Lu; Chatterjee, Nilanjan; Hu, Frank B; Kraft, Peter
- Year
- 2012
- Journal
- American journal of epidemiology
- PMID
- 22199026
- DOI
- 10.1093/aje/kwr368
- PMCID
- PMC3261439
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.
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