biologically. This brings its own set of complications, as decisions must be made about the nature of genetic effects across the pathway or network: is a mutation in any of the genes in the network sufficient? Are all variations within the network expected to have an equal effect on outcome? Are mutations across multiple genes in the network acting cumulatively to affect outcome? Similar questions can be asked about multiple variants within any given gene of interest. Should polygenic risk scores that capture risk across the genome be used? The answer to these questions depends on the investigator’s theory behind how the environment is operating: does the investigator believe that all genes involved in outcome should be moderated by that environment in a parallel fashion or only subsets of the relevant genes? There is no straightforward answer to these questions, but what is clear is that deeper thought must be given to these issues in order to move the study of cGxE forward. Justification for the choices made in any given GxE study should be included in the publication. Because it is challenging to keep up with advances in the field of genetics, we suggest that this is an area
