Efficient Genome-Wide Association Testing of Gene-Environment Interaction in Case-Parent Trios

Complex trait variation is likely to be explained by the combined effects of genes, environmental factors, and gene x environment (G x E) interaction. The authors introduce a novel 2-step method for detecting a G x E interaction in a genome-wide association study (GWAS) of case-parent trios. The method utilizes 2 sources of G x E information in a trio sample to construct a screening step and a testing step. Across a wide range of models, this 2-step procedure provides substantially greater power to detect G x E interaction than a standard test of G x E interaction applied genome-wide. For example, for a disease susceptibility locus with minor allele frequency of 15%, a binary exposure variable with 50% prevalence, and a GWAS scan of 1 million markers in 1,000 case-parent trios, the 2-step method provides 87% power to detect a G x E interaction relative risk of 2.3, as compared with only 25% power using a standard G x E test. The method is easily implemented using standard software. This 2-step scan for G x E interaction is independent of any prior scan that may have been conducted for genetic main effects, and thus has the potential to uncover new genes in a GWAS that have not been previously identified.