Two-stage strategies to detect gene × gene interactions in case-control data

Large genetic association studies based on hundreds of thousands of single-nucleotide polymorphisms (SNPs) are a popular option for the study of complex diseases. The evaluation of gene × gene interactions in such studies is a sensible method of capturing important genetic effects. The number of tests required to consider all pairs of SNPs, however, can lead to a computational burden, and efficient strategies to reduce the number of tests performed are desirable. In this study, we compare two-stage strategies for pairwise SNP interactions testing. Those approaches rely on the selection of SNPs based on the single-locus test results obtained at the first stage. In the simultaneous approach, SNPs that fall below the marginal significance thresholds (p = 0.05 and p = 0.1) in stage 1 are selected and tested for within-group pairwise interaction in stage 2. With the conditional approach, SNPs that reach Bonferroni-adjusted significance at the first stage are tested in pairwise combinations with all SNPs in the data set. We compared the performance of those strategies by using Replicate 1 of the simulated data set of the Genetic Analysis Workshop 15 Problem 3. Most interactions detected resulted from SNP pairs within 1000 kb of each other. The remaining were false positives involving SNPs with excessively strong marginal signals. Our results highlight the need to account for locus proximity in the evaluation of interaction effects and emphasize the importance of marginal signal strength in logistic regression-based interaction modeling. We found that modeling additive genetic effects alone was sufficient to capture underlying dominance interaction effects in the data.