Figure 1. Graphical illustration of the framework of gene-based single-marker test and its generalization to a gene-based gene–gene interaction (GGG) test as proposed in this paper.

While the former considers the P values of each single-marker test (A), a GGG test (B) is based on all P values of an interaction test between each pair of markers from each of the two genes. In order to combine these pairwise P values into a single test, a correlation matrix that concurrently accounts for linkage disequilibrium in each of the two genes needs to be estimated, which we derive in Materials and Methods.