There has been a proliferation of studies on gene-environment interaction in recent years, in both candidate gene and GWAS. Most studies in this large and growing literature use a cross-product term to model interaction between a genotype and environmental variable. In the case of binary variables, such as genotype of males on the X chromosome, the use of the cross-product term is appropriate. For loci with very low minor allele frequencies, such that no homozygotes for the minor allele exist in the population, this simple model also yields unbiased results. In all other cases, i.e., where three genotype categories exist, the cross-product approach should be avoided. This is because when three genotype categories exist (0, 1, 2), the use of the only one cross-product term only reproduces interaction effects accurately under certain very unusual circumstances. When the minor allele frequency is low, say 10 % then about 1 % of data is expected as rare homozygous. In this case the majority of data will lay on other two strata and the model with only one cross product term can reflect
