Incorporating Gene-Environment Interaction in Testing for Association with Rare Genetic Variants

Abstract

Objectives: The incorporation of gene-environment interactions could improve the ability to detect genetic associations with complex traits. For common genetic variants, single-marker interaction tests and joint tests of genetic main effects and gene-environment interaction have been well-established and used to identify novel association loci for complex diseases and continuous traits. For rare genetic variants, however, single-marker tests are severely underpowered due to the low minor allele frequency, and only a few gene-environment interaction tests have been developed. We aimed at developing powerful and computationally efficient tests for gene-environment interaction with rare variants. Methods: In this paper, we propose interaction and joint tests for testing gene-environment interaction of rare genetic variants. Our approach is a generalization of existing gene-environment interaction tests for multiple genetic variants under certain conditions. Results: We show in our simulation studies that our interaction and joint tests have correct type I errors, and that the joint test is a powerful approach for testing genetic association, allowing for gene-environment interaction. We also illustrate our approach in a real data example from the Framingham Heart Study. Conclusion: Our approach can be applied to both binary and continuous traits, it is powerful and computationally efficient.