biostudies-literatureKawaguchi ESNational Institute of Environmental Health SciencesNIEHS NIH HHSNCI NIH HHS152-166https://www.ebi.ac.uk/biostudies/studies/S-EPMC9974838biostudies-literatureUnknown47(2)Two-step tests for gene-environment ( G×E$G\times E$ ) interactions exploit marginal single-nucleotide polymorphism (SNP) effects to improve the power of a genome-wide interaction scan. They combine a screening step based on marginal effects used to "bin" SNPs for weighted hypothesis testing in the second step to deliver greater power over single-step tests while preserving the genome-wide Type I error. However, the presence of many SNPs with detectable marginal effects on the trait of interest can reduce power by "displacing" true interactions with weaker marginal effects and by adding to the number of tests that need to be corrected for multiple testing. We introduce a new significance-based allocation into bins for Step-2 G×E$G\times E$ testing that overcomes the displacement issue and Genetic epidemiologyImproved two-step testing of genome-wide gene-environment interactions.PMC9974838R01 CA201407P01 CA196569T32 ES013678P30 ES007048Kim AEGauderman WJKawaguchi ESLewinger JPfalseImproved two-step testing of genome-wide gene-environment interactions.Two-step tests for gene-environment ( G×E$G\times E$ ) interactions exploit marginal single-nucleotide polymorphism (SNP) effects to improve the power of a genome-wide interaction scan. They combine a screening step based on marginal effects used to "bin" SNPs for weighted hypothesis testing in the second step to deliver greater power over single-step tests while preserving the genome-wide Type I error. However, the presence of many SNPs with detectable marginal effects on the trait of interest can reduce power by "displacing" true interactions with weaker marginal effects and by adding to the number of tests that need to be corrected for multiple testing. We introduce a new significance-based allocation into bins for Step-2 G×E$G\times E$ testing that overcomes the displacement issue and 2023-01-01T00:00:00Z2023 Mar2025-04-03T23:50:12.006Z2025-04-03T23:50:12.006ZS-EPMC99748383657116210.1002/gepi.22509