Figure 1.

To understand the etiology of disease, we have to understand how genotypic variation transduces into whole-organism phenotypic variation. Gene-environment interactions have long been recognized as a fundamental component of this process. However, robust demonstrations of gene-environment effects in humans are scarce. Illuminating the mechanistic black box leading from genes to disease by characterizing variation at each – omics level and by capitalizing on the advantages and power gained from the use of endophenotypes holds the promise to address this major shortcoming in modern human biology.