Research Article: Working memory reflects vulnerability to early life adversity as a risk factor for substance use disorder in the FKBP5 cortisol cochaperone polymorphism, rs9296158

Date Published: June 11, 2019

Publisher: Public Library of Science

Author(s): William R. Lovallo, Ashley Acheson, Andrew J. Cohoon, Kristen H. Sorocco, Andrea S. Vincent, Colin A. Hodgkinson, David Goldman, Alexandra Kavushansky.


Early life adversity (ELA) negatively affects health behaviors in adulthood, but pathways from ELA exposure to behavioral outcomes are poorly understood. ELA in childhood and adolescence may translate into adult outcomes by way of modified glucocorticoid signaling. The cortisol cotransporter, FKBP5 has a G-to-A substitution (rs9296158) that hinders cortisol trafficking within target cells, and this impaired glucocorticoid signaling may shape the long-term response to ELA. We used performance on the Stroop test to assess working memory in 546 healthy young adults who had experienced 0, 1, or > 1 forms of ELA in childhood and adolescence and were genotyped for the FKBP5 rs9296158 G-to-A polymorphism. We observed a robust Gene x Environment interaction (F = 9.49, p < .0001) in which increased ELA exposure led to progressively greater Stroop interference in persons carrying AG and AA genotypes of FKBP5 with no such effect in GG carriers. Further work is needed to explore the modification of cognitive function resulting from ELA. Impairments in working memory illustrate how ELA may use glucocorticoid pathways to influence working memory with potential implications for decision-making and risky behavior including substance use disorders.

Partial Text

Exposure to early life adversity (ELA) may impair health and increase the risk for psychiatric disorders [1]. ELA exposure during childhood and adolescence affects the stress axis in early adulthood [2] and also leads to modifications of cognitive function and regulation of affect [3]. Importantly, not all persons are equally vulnerable to ELA [4, 5] suggesting that gene-by-environment (G x E) interactions may play a role in determining how ELA leads to behavioral outcomes relative to health.

Demographic and other descriptive information for AA/AG and GG allele carriers is provided in Table 1. Groups with higher levels of ELA exposure were more likely to be female and to have lower socioeconomic status scores, fewer years of education, and lower Shipley mental age scores.

The results replicated our earlier finding of a G x E impact of ELA exposure on executive components of working memory in carriers of the minor, A-allele, rs9296158 on FKBP5 [23]. A-allele carriers in both the earlier and the new subsamples displayed larger Stroop interference scores than their GG-allele counterparts (Fig 1 top panels) supporting the reliability of an FKBP5 genotype effect on components of working memory, in agreement with a study in older adults [41]. The replicated results indicate that executive function processes appear to be malleable by early experience in carriers of the FKBP5 A allele (rs9296158).

Persons carrying one or two copies of the variant, A allele of the molecular cochaperone protein, FKBP5 appear to be vulnerable to impact of ELA on executive functions, while their GG-allele counterparts appear to be unaffected. Impaired cellular trafficking of cortisol in A-allele carriers may illustrate a point of systems response to ELA that exerts a deleterious effect in adulthood. This G x E effect appeared here as a modest impairment of working memory performance, thereby implicating glucocorticoid actions in working memory systems, including the prefrontal cortex and the temporoparietal region, as targets for study in A-allele carriers exposed to ELA during childhood and adolescence. Further work is needed to understand the molecular and cellular points of intersection connecting ELA with glucocorticoid mechanisms that affect the central nervous system.