Deciphering Genome Environment Wide Interactions Using Exposed Subjects Only

The recent successes of genome-wide association studies (GWAS) have renewed interest in genome environment wide interaction studies (GEWIS) to discover genetic factors that modulate penetrance of environmental exposures to human diseases. Indeed, gene-environment interactions (G × E), which have not been emphasized in the GWAS era, could be a source contributing to the missing heritability, a major bottleneck limiting continuing GWAS successes. In this manuscript, we describe a design and analytic strategy to focus on G × E using only exposed subjects, dubbed as e-GEWIS. Operationally, an e-GEWIS analysis is equivalent to a GWAS analysis on exposed subjects only, and it has actually been used in some earlier GWAS without being explicitly identified as such. Through both analytics and simulations, e-GEWIS has been shown better efficiency than the usual cross-product-based analysis of G × E interaction with both cases and controls (cc-GEWIS), and they have comparable efficiency to case-only analysis of G × E (c-GEWIS), with potentially smaller sample sizes. The formalization of e-GEWIS here provides a theoretical basis to legitimize this framework for routine investigation of G × E, for more efficient G × E study designs, and for improvement of reproducibility in replicating GEWIS findings. As an illustration, we apply e-GEWIS to a lung cancer GWAS data set to perform a GEWIS, focusing on gene and smoking interaction. The e-GEWIS analysis successfully uncovered positive genetic associations on chromosome 15 among current smokers, suggesting a gene-smoking interaction. Although this signal was detected earlier, the current finding here serves as a positive control in support of this e-GEWIS strategy.