Although most G×E research uses candidate genes, environmental exposures can also be used to discover novel loci. Indeed, one possible reason for the paucity of susceptibility genes in psychiatry is that gene-discovery studies have been searching for genetic effects on disease rather than for genetic effects on vulnerability to environmental causes of disease (130). Whereas in genetic association studies, a candidate gene is a gene suspected of being involved in a trait or disease—either because its protein product is relevant or because it has been uncovered in the course of association or linkage analysis of the phenotype—in G×E research a candidate gene is one plausibly related to the organisms’ reactivity to the environmental risk or pathogen (131). The idea that genes may moderate the effect of environmental risk has direct implications for hypothesis-driven selection of novel candidate genes. For example, genes associated with the physiological response to psychological stress, particularly in the HPA axis, are natural candidates for G×E research on stress and depression (132). Genes regulated by hypoxia are candidates for G×E research on obstetric complications and schizophrenia (133).
