The Differential Susceptibility Hypothesis: Sensitivity to the Environment for Better and for Worse

Opinion EDITORIAL The Differential Susceptibility Hypothesis Sensitivity to the Environment for Better and for Worse Jay Belsky, PhD It has long been appreciated by those studying diverse aspects of health and human development that some indi- viduals may be more vulnerable to adversity than others. That is, because of some personal attribute(s) that could be ge- netic, physiologic, and/or be- havioral in character, some Related article children and adults are more likely than others to succumb to the negative effects of prob- lematic environmental conditions (eg, poverty, malnutrition, or pathogen exposure). Research on obesity, the focus of the article by Silveira et al 1 in this issue of JAMA Pediatrics, cer- tainly raises this issue given, on the one hand, genome-wide association study findings highlighting obesity genes 2 and, on the other hand, research calling attention to the obesogenic con- sequences of growing up in a community or society in which fat intake is especially high. 3 Collectively, such work raises the prospect that, in a gene-environment interaction, the adverse effect of exposure to such environmental conditions will be es- pecially, if not exclusively, evident among those individuals car- rying more rather than fewer obesity genes. This classic vulnerability framework, based as it is on dual- risk conditions, has been challenged by evolutionary- minded scholars who contend that the individuals most vul- nerable to adversity are most likely to benefit from supportive or enriched—or even just benign—contextual conditions. 4,5 In- deed, the claim has been made by those embracing this dif- ferential susceptibility (to environmental influences) hypoth- esis that a medical or pathologic model, focused as it is on disease and dysfunction, is problematic because it risks mis- construing general plasticity or malleability in response to good and bad contextual conditions as vulnerability to adversity. This risk arises because so much health-related research has fo- cused exclusively—even if for understandable, humanitarian reasons—on risk factors associated with disease and disorder phenotypes. Had this work also measured supportive envi- ronmental conditions and good health—not just the absence of adversity and disease—it would have discovered that the very same individual attributes, including genotype, that predis- pose one to develop or function poorly under adverse condi- tions also predispose one to develop or function especially well under positive circumstances. In other words, there are indi- vidual differences in plasticity or malleability that operate in a for-better-and-for-worse manner 6 depending on the circum- stances in which a child grows up or an individual finds him- self or herself. Thus, although some people are highly sensi- tive and responsive to their environment, good or bad, others are much less so. jamapediatrics.com jamanetwork/2016/ped/02_01_2016/ped150040pap There is increasing evidence, especially within the behav- ioral sciences, consistent with this claim. 7 Indeed, it was ap- preciation of this body of work chronicling differential sus- ceptibility to environmental influence that informed the genotypic focus of the study by Silveira et al. 1 Even though DRD4 has not been directly linked to obesity, it has been re- peatedly found to operate as a plasticity factor, making indi- viduals more or less responsive to positive and negative con- textual conditions. In fact, not only did the long or 7-repeat allele emerge in the meta-analysis by van Ijzendoorn and Bakermans-Kranenburg 8 of research on dopaminergic gene- environment interactions in children as being associated with greater and lesser responsiveness to a variety of contextual con- ditions, but also data consistent with this observation have emerged in randomized clinical trials of gene-intervention in- teractions. Thus, for example, Beach et al 9 found that the Strong African American Families’ intervention resulted in the prevention of adolescent substance use, principally among 7-repeat carriers. What findings, such as those that informed the work by Silveira et al, 1 on fat intake indicate is that certain genes may make individuals more or less sensitive to diverse environ- mental conditions. In fact, it is for this reason that these in- vestigators predicted—and found—that girls (but not boys) car- rying the 7-repeat allele of DRD4 derived the most calories from fat of all children if they lived in more economically disadvan- taged families but the least calories if they grew up in more eco- nomically advantaged ones. Fat consumption proved to be un- related to such family circumstances among children who did not carry the putative, 7-repeat plasticity allele. Thus, whereas some children proved highly susceptible to environmental con- ditions—for better and for worse—others appeared not to be affected at all. In observational and intervention research, DRD4 is not the only polymorphism found to operate as a plasticity gene. 6,10 In fact, in 1 study 11 of the efficacy of a lifestyle intervention for obese children, only those carrying the C allelic variant of the DRD2 gene evinced noteworthy body mass index (calculated as weight in kilograms divided by height in meters squared) change (ie, not TT homozygotes). What data like these imply is that it would be a mistake to think exclusively in terms of one gene at a time and thus of individuals being malleable or not. Because many genes contribute to child and adult sensi- tivity and responsiveness to the environment, plasticity is bet- ter conceptualized as a gradient, with some individuals being more and some less responsive to environmental conditions, rather than categorically, with some being malleable and oth- (Reprinted) JAMA Pediatrics Published online February 1, 2016 PAGE: right 1 SESS: 13 Downloaded From: http://archpedi.jamanetwork.com/ by a University of California - Davis User on 02/01/2016 E1 OUTPUT: Jan 15 14:32 2016