Subset-Based Analysis Using Gene-Environment Interactions for Discovery of Genetic Associations across Multiple Studies or Phenotypes

Objectives: Classical methods for combining summary data from genome-wide association studies only use marginal genetic effects, and power can be compromised in the presence of heterogeneity. We aim to enhance the discovery of novel associated loci in the presence of heterogeneity of genetic effects in subgroups defined by an environmental factor. Methods: We present a pvalue-assisted subset testing for associations (pASTA) framework that generalizes the previously proposed association analysis based on subsets (ASSET) method by incorporating gene-environment (G-E) interactions into the testing procedure. We conduct simulation studies and provide two data examples. Results: Simulation studies show that our proposal is more powerful than methods based on marginal associations in the presence of G-E interactions and maintains comparable power even in their absence. Both data examples demonstrate that our method can increase power to detect overall genetic associations and identify novel studies/phenotypes that contribute to the association. Conclusions: Our proposed method can be a useful screening tool to identify candidate single nucleotide polymorphisms that are potentially associated with the trait(s) of interest for further validation. It also allows researchers to determine the most probable subset of traits that exhibit genetic associations in addition to the enhancement of power.