Practice of Epidemiology Efficient Genome-Wide Association Testing of Gene-Environment Interaction

Complex trait variation is likely to be explained by the combined effects of genes, environmental factors, and gene 3 environment (G 3 E) interaction. The authors introduce a novel 2-step method for detecting a G 3 E interaction in a genome-wide association study (GWAS) of case-parent trios. Themethod utilizes 2 sources ofG3E 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 3 E interaction than a standard test of G 3 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 aG3 E interaction relative risk of 2.3, as compared with only 25% power using a standardG3 E test. Themethod is easily implemented using standard software. This 2-step scan for G3 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. environmental exposure; epidemiologic methods; genetic association studies; genetics; genome-wide association study; models, genetic Abbreviations: DSL, disease susceptibility locus; G-E, gene-environment; G 3 E, gene 3 environment; GWAS, genome-wide association study(ies); SNP, single nucleotide polymorphism