FKBP5 and emotional neglect interact to predict individual differences in amygdala reactivity

Abstract

Individual variation in physiological responsiveness to stress mediates risk for mental illness and is influenced by both experiential and genetic factors. Common polymorphisms in the human gene for FK506 binding protein 5 (FKBP5), which is involved in transcriptional regulation of the hypothalamic-pituitary-adrenal (HPA) axis, have been shown to interact with childhood abuse and trauma to predict stress-related psychopathology. In the current study, we examined if such gene-environment interaction effects may be related to variability in the threat-related reactivity of the amygdala, which plays a critical role in mediating physiological and behavioral adaptions to stress including modulation of the HPA axis. To this end 139 healthy, Caucasian youth completed a BOLD fMRI probe of amygdala reactivity and self-report assessments of emotional neglect (EN) and other forms of maltreatment. These individuals were genotyped for six FKBP5 polymorphisms (rs7748266, rs1360780, rs9296158, rs3800373, rs9470080, and rs9394309) previously associated with psychopathology and/or HPA axis function. Interactions between each SNP and EN emerged such that risk alleles predicted relatively increased dorsal amygdala reactivity in the context of higher EN, even after correcting for multiple testing. Two different haplotype analyses confirmed this relationship as haplotypes with risk alleles also exhibited increased amygdala reactivity in the context of higher EN. Our results suggest that increased threat-related amygdala reactivity may represent a mechanism linking psychopathology to interactions between common genetic variants affecting HPA axis function and childhood trauma.

Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume

“…The present study is in accordance with a recent finding demonstrating a G 9 E interaction of FKBP5 with EN on amygdala activity (White et al 2012). In both our study and that of White et al (2012), homozygotes for the rs1360780 T allele showed increasing activity in the right amygdala with the level of childhood neglect, while C homozygotes exhibited decreasing activity, with heterozygotes being intermediate.…”

“…In both our study and that of White et al (2012), homozygotes for the rs1360780 T allele showed increasing activity in the right amygdala with the level of childhood neglect, while C homozygotes exhibited decreasing activity, with heterozygotes being intermediate. However, in contrast to White et al (2012), who found a significant increase in T homozygotes, a significant decrease in C homozygotes was obtained in our study. Several reasons may be responsible for this discrepancy, such as differences in sample composition, reported level of EN, and implementation of the imaging paradigm employed.…”

“…Several reasons may be responsible for this discrepancy, such as differences in sample composition, reported level of EN, and implementation of the imaging paradigm employed. Moreover, in our study, a prospectively ascertained objective measure of childhood adversity was included, while this was not the case in the White et al (2012) study. In contrast to the retrospective CTQ self-report, this measure yielded only weak effects on amygdala activity and connectivity.…”

“…Considering FKBP5, recent evidence indicates that rs1360780 interacts with childhood adversity to predict amygdala activity in adolescents (White et al 2012). While in T homozygotes, activity in the right amygdala increased with the level of emotional neglect (EN), no such effect was observed in C homozygotes.…”

“…The CTQ yields a total score and subscale scores for each type of maltreatment. Based on previous research (e.g., White et al 2012), we focused on the subscale of emotional neglect (EN) and, additionally, included the total score.…”