In a recent commentary on gene × environment (GxE) interactions in Molecular Psychiatry, Belsky et al.1 argue that many GxE findings are misinterpreted through adherence to a dominant model of disease vulnerability that assumes an ordinal interaction between specific genetic variation and the presence/absence of environmental adversity (diathesis stress). They cite numerous studies of people with putative ‘risk’ alleles of certain monoamine-regulating polymorphisms who experience psychiatric outcomes (for example, depression) more frequently in adverse circumstances, yet less frequently in salutary environments, compared with those with other genotypes. Belsky et al. suggest that this cross-over (or disordinal) interaction reflects ‘differential susceptibility’ to environmental influences (heightened plasticity) among individuals possessing these alleles (‘differential’ denoting the potential for both worse and better outcomes), rather than genetic vulnerability to outcomes that are specifically negative and expressed only in adversity. Differential susceptibility has distinct parallels in the ‘reaction norm’ (RN), a concept introduced by Woltereck in 1909 and a staple of experimental research in biology and evolutionary genetics. Here, I suggest that framing differential susceptibility within an RN perspective clarifies the role of phenotypic plasticity in GxE interaction.
How is phenotypic plasticity related to GxE interaction? First, plasticity (great or small) is a property of a genotype and is therefore unrelated to the RNs of other genotypes. The plasticity of genotype ‘a,’ for example, is the same whether in interaction with ‘b’ or with ‘c.’ Second, only the intersection of RNs distinguishes disordinal from ordinal GxE (not, for instance, a greater difference in relative plasticity between interacting genotypes). And third, the ‘for worse and better’ argument of Belsky et al.—the differential part of differential susceptibility—demands only that different genotypes produce the same phenotype at an intermediate location along an environmental gradient (that is, disordinal GxE). As the authors anticipate, disordinal GxE may be common but elude detection if the measured phenotype and environment reflect only a portion of their natural ranges. If the axes in the figure could be lengthened meaningfully (dashed lines), the RNs of genotypes ‘a’ and ‘c’ would eventually cross. Thus, the generality of disordinal GxE rests importantly on understanding the natural ranges of environmental variation (for example, whether positive parenting is coextensive dimensionally with negative parenting) and of behavioral phenotypes (for example, whether positive and negative affect are ends of a bipolar continuum or are independent).
This is a preview of subscription content, access via your institution