Exploring Genetic Interactions with Rare Variants Reveals Gene Networks Susceptible to Complex Diseases

Genetic interactions play a crucial role in understanding the susceptibility and etiology of complex human diseases. However, existing methods for analyzing gene-gene interactions are often limited to common variants and may not capture the effects of rare variants. In this study, we propose a novel method called GGI-RUNNER that is specifically designed for analyzing gene-gene interactions of rare variants. GGI-RUNNER evaluates the enrichment of rare variant interaction burden in patients relative to baselines in the general population. The baselines are estimated for pairwise genes by a recursive truncated negative-binomial regression model on multiple genomic features available from public data. Intensive simulations demonstrate that GGI-RUNNER exhibits substantially higher statistical power than alternative epistasis tests and maintains reasonable type I error rates even in stratified populations. Applied to real data, GGI-RUNNER identified significant rare variant interactions associated with Alzheimer’s disease, Hirschsprung’s disease, Ulcerative colitis and Crohn’s disease. Furthermore, we found that these identified genes for each trait can form interconnected networks, which may provide valuable insights into the underlying molecular mechanisms.