Poor statistical power in population-based association study of gene interaction

Abstract

Abstract Background Statistical epistasis, or “gene–gene interaction” in genetic association studies, means the nonadditive effects between the polymorphic sites on two different genes affecting the same phenotype. In the genetic association analysis of complex traits, nevertheless, the researchers haven’t found enough clues of statistical epistasis so far. Methods We developed a statistical model where the statistical epistasis was presented as an extra linkage disequilibrium between the polymorphic sites of different risk genes. The power of statistical test for identifying the gene–gene interaction was calculated and then compared in different hypothesis scenarios. Results Our results show the statistical power increases with the increasing of interaction coefficient, relative risk, and linkage disequilibrium with genetic markers. However, the power of interaction discovery is much lower than that of regular single-site association test. When rigorous criteria were employed in statistical tests, the identification of gene–gene interaction became a very difficult task. Since the criterion of significance was given to be p-value ≤ 5.0 × 10–8, the same as that of many genome-wide association studies, there is little chance to identify the gene–gene interaction in all kind of circumstances. Conclusions The lack of epistasis tends to be an inevitable result caused by the statistical principles of methods in the genetic association studies and therefore is the inherent characteristic of the research itself.