SNPs are followed up in G×E interaction testing. Several Group 10 contributions showed that the use of this strategy may miss potentially important SNPs that have a very small main effect, but a significant G×E effect. For example, Arya et al. [2009] tested genotype×sex interactions for association with RA and found 30 SNP×sex interactions that were nominally significant (p<1.0×10−4), but none of these were significant in the single-SNP analysis. Similarly, Zhuang and Morris [2009] also tested genotype×sex interactions for association with RA and identified eight novel SNPs that demonstrated genetic effects in only one sex, or reciprocal effects on risk in males and females, but these SNPs were not significant in the single-SNP analysis. In the FHS, Maenner et al. [2009] found significant evidence for an interaction between smoking and a SNP selected by a RF algorithm as the most important, but this SNP ranked as only the 2,111th smallest p-value in the single-SNP analysis (out of 355,649 SNPs).
