Identification of interacting genes in genome-wide association studies using a model-based two-stage approach.

In this paper, we propose a two-stage approach based on 17 biologically plausible models to search for two-locus combinations that have significant joint effects on the disease status in genome-wide association (GWA) studies. In the two-stage analyses, we only test two-locus joint effects of SNPs that show modest marginal effects. We use simulation studies to compare the power of our two-stage analysis with a single-marker analysis and a two-stage analysis by using a full model. We find that for most plausible interaction effects, our two-stage analysis can dramatically increase the power to identify two-locus joint effects compared to a single-marker analysis and a two-stage analysis based on the full model. We also compare two-stage methods with one-stage methods. Our simulation results indicate that two-stage methods are more powerful than one-stage methods. We applied our two-stage approach to a GWA study for identifying genetic factors that might be relevant in the pathogenesis of sporadic Amyotrophic Lateral Sclerosis (ALS). Our proposed two-stage approach found that two SNPs have significant joint effect on sporadic ALS while the single-marker analysis and the two-stage analysis based on the full model did not find any significant results.