Robustness of meta-analyses in finding gene × environment interactions

Meta-analyses that synthesize statistical evidence across studies have become important analytical tools for genetic studies. Inspired by the success of genome-wide association studies of the genetic main effect, researchers are searching for gene × environment interactions. Confounders are routinely included in the genome-wide gene × environment interaction analysis as covariates; however, this does not control for any confounding effects on the results if covariate × environment interactions are present. We carried out simulation studies to evaluate the robustness to the covariate × environment confounder for meta-regression and joint meta-analysis, which are two commonly used meta-analysis methods for testing the gene × environment interaction or the genetic main effect and interaction jointly. Here we show that meta-regression is robust to the covariate × environment confounder while joint meta-analysis is subject to the confounding effect with inflated type I error rates. Given vast sample sizes employed in genome-wide gene × environment interaction studies, non-significant covariate × environment interactions at the study level could substantially elevate the type I error rate at the consortium level. When covariate × environment confounders are present, type I errors can be controlled in joint meta-analysis by including the covariate × environment terms in the analysis at the study level. Alternatively, meta-regression can be applied, which is robust to potential covariate × environment confounders.