Smooth-threshold multivariate genetic prediction incorporating gene–environment interactions

Abstract

We propose a genetic prediction modeling approach for genome-wide association study (GWAS) data that can include not only marginal gene effects but also gene-environment (GxE) interaction effects—i.e., multiplicative effects of environmental factors with genes rather than merely additive effects of each. The proposed approach is a straightforward extension of our previous multiple-regression-based method, STMGP (smooth-threshold multivariate genetic prediction), with the new feature being that genome-wide test statistics from a GxE interaction analysis are used to weight the corresponding variants. We develop a simple univariate regression approximation to the GxE interaction effect that allows a direct fit of the STMGP framework without modification. The sparse nature of our model automatically removes irrelevant predictors (including variants and GxE combinations), and the model is able to simultaneously incorporate multiple environmental variables. Simulation studies to evaluate the proposed method in comparison with other modeling approaches demonstrate its superior performance under the presence of GxE interaction effects. We illustrate the usefulness of our prediction model through application to real GWAS data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Data-Adaptive Multivariate Test for Genomic Studies Using Fused Lasso

“…Furthermore, the type I error is controlled without normality assumption on error distribution, if the number of explanatory variables is sufficiently large [20]. Although, in this paper, the testing framework is demonstrated for linear or additive model for variants, it is in principle applicable to nonlinear models such as the genetic models involving interaction terms, e.g., gene-gene interaction and gene-environment interaction as in [19,47]. Other potential applications include association studies with many phenotypes called PheWAS [48] and those with high-dimensional nuisance parameters [49].…”