Another challenge is obtaining an appropriate replication population. Differences in the underlying distribution of environmental exposures, LD structures, and genetic modifiers can reduce the power to detect an interaction in independent studies. In cases where an investigator is examining a rare disease, genetic, or environmental exposure; where exposures are unique to particular populations; or where the initial finding was obtained within a large consortium comprising all known studies of a specific outcome, an appropriate replication population may not exist [Mechanic, et al. 2012]. Potential differences in the method or timing of assessment of an environmental exposures or measurement of genetic variants (e.g. genotyping platform coverage) may also reduce the suitability of potential replication populations for a specific GxE interaction.
