A related question is whether or not genotype-by-environment interactions at the level of transcription are necessary to explain genotype-by-environment interactions for disease. It is possible the small interactions beneath the level of detection of GWAS are prevalent, or alternatively that disease arises primarily as a result of rare alleles of major effect, whose penetrance may be modulated in an environment-specific manner. However, transcriptional interactions are not required to explain the increased incidence of chronic disease. It is not difficult to imagine that individuals that fall into the major categories of transcriptome profiles (such as those implicated in Fig. 4 and Supplementary Fig. 4 online) have different distributions of disease susceptibility that alter the genotype-disease association matrix genome-wide, thereby inducing environment-by-genotype interactions for disease. Transcription of some genes that contribute to this expression component may also correlate with disease directly, effectively uncovering cryptic variation and resulting in environment-specific eSNP disease associations without any interaction effect at the level of transcription (Fig. 6)39. A corollary of this is that gene expression profiling might be used to stratify individuals at elevated risk for
