GWGGI: software for genome-wide gene-gene interaction analysis

Background: While the importance of gene-gene interactions in human diseases has been well recognized, identifying them has been a great challenge, especially through association studies with millions of genetic markers and thousands of individuals. Computationally efficient and powerful tools are in great need for the identification of new gene-gene interactions in high-dimensional association studies. Result: We develop C++ software for genome-wide gene-gene interaction analyses (GWGGI). GWGGI utilizes tree-based algorithms to search a large number of genetic markers for a disease-associated joint association with the consideration of high-order interactions, and then uses non-parametric statistics to test the joint association. The package includes two functions, likelihood ratio Mann-Whitney (LRMW) and Tree Assembling Mann-Whitney (TAMW). We optimize the data storage and computational efficiency of the software, making it feasible to run the genome-wide analysis on a personal computer. The use of GWGGI was demonstrated by using two real data-sets with nearly 500 k genetic markers. Conclusion: Through the empirical study, we demonstrated that the genome-wide gene-gene interaction analysis using GWGGI could be accomplished within a reasonable time on a personal computer (i.e., similar to 3.5 hours for LRMW and similar to 10 hours for TAMW). We also showed that LRMW was suitable to detect interaction among a small number of genetic variants with moderate-to-strong marginal effect, while TAMW was useful to detect interaction among a larger number of low-marginal-effect genetic variants.