High-Dimensional Gene–Environment Interaction Analysis

Beyond the main genetic and environmental effects, gene–environment (G–E) interactions have been demonstrated to significantly contribute to the development and progression of complex diseases. Published analyses of G–E interactions have primarily used a supervised framework to model both low-dimensional environmental factors and high-dimensional genetic factors in relation to disease outcomes. In this article, we aim to provide a selective review of methodological developments in G–E interaction analysis from a statistical perspective. The three main families of techniques are hypothesis testing, variable selection, and dimension reduction, which lead to three general frameworks: testing-based, estimation-based, and prediction-based. Linear- and nonlinear-effects analysis, fixed- and random-effects analysis, marginal and joint analysis, and Bayesian and frequentist analysis are reviewed to facilitate the conduct of interaction analysis in a wide range of situations with various assumptions and objectives. Statistical properties, computations, applications, and future directions are also discussed.