Identifying gene-environment interactions across genome-wide, twin, and polygenic risk score approaches

We highlight a high degree of consistency across approaches, with each method detecting GxE. Specifically, genome-wide approaches identify individual variants that interact with an environmental moderator, but struggle with low statistical power when a trait is highly polygenic. Alternatively, aggregating genome-wide effects from a discovery sample into a PRS in the target sample increases the ability to detect broad genetic effects. However, if the statistical power in the discovery sample is low, the associations with the PRS tend to underestimate the genetic signal. This is true for both genetic main and interaction effects. Finally, twin studies are generally robust to differences in polygenicity as well as the underlying distributions of the genetic main and interaction effects. The ability of all three methods to robustly identify genomic moderation emphasizes the fact that multiple valid ways to detect GxE exist that stem from the same basic assumptions about the genetic architecture of complex traits.