Abstract Triglycerides are an important measure of heart health. Although more than 90 genes have been found to be associated to lipids, they only explain 12 to 15% of the variance in lipid levels. Evidence suggests that age may interact with the genetic effect on lipid levels. Existing methods to detect the main effect of rare variants cannot be readily applied for testing the gene environment interaction effect of rare variants, as those methods either have unstable results or inflated Type I error rates when the main effect exists. To overcome these difficulties, we developed two statistical methods: testing of optimally weighted combination of single-nucleotide polymorphism (SNP) environment interaction (TOW-SE) and a variable weight TOW-SE (VW-TOW-SE) to test the gene environment interaction effect of rare variants by grouping SNPs into biologically meaningful SNP-sets (SNPs in a gene or pathway) to improve power and interpretability. The proposed methods can be applied to either continuous or binary environmental variables, and to either continuous or binary outcomes. Simulation studies show that Type I error rates of the proposed methods are under control. Comparing the two methods with the existing interaction sequence kernel association test (iSKAT), the VW-TOW-SE is the most powerful test and the TOW-SE is the second most powerful test when gene environment interaction effect exists for both rare and common variants. The three tests were applied to the GAW20 simulated data, among the five regions in which the main effect of common SNPs was simulated and the gene–age interaction effect was not included. As expected, none of the tests indicated positive results.
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