The new generation of purpose-built Gene-Environment-Wide Interaction studies may be an improvement over opportunistic studies published in these early years of G×E research, but even these will fall short unless they attend to the measurement of environmental exposures. An alternative is to pursue study designs that use confirmed environmental effects on disease. Such “exposed-only designs” will test genome-wide associations comparing equally exposed individuals who do versus do not develop a disease in order to discover novel susceptibility loci. Examples of this design can be seen in research on infectious disease, whose starting point is pathogen exposure (138). The environmental risks (i.e., pathogens) for many psychiatric conditions are well established, if not always well measured. As such, the strong prior probabilities for environmental risks can be harnessed in psychiatry to design genome-wide studies focused on identifying genetic differences in responses to well-defined environmental risks. This approach to gene discovery will involve entirely different designs and sampling frames than currently used in case-control studies and biobanks.
