Moderation of Adult Depression by a Polymorphism in the FKBP5 Gene and Childhood Physical Abuse in the General Population

Abstract

Childhood maltreatment and depressive disorders have both been associated with a dysregulation of the hypothalamic-pituitary-adrenal axis. The FKBP5 gene codes for a co-chaperone regulating the glucocorticoid-receptor sensitivity. Previous evidence suggests that subjects carrying the TT genotype of the FKBP5 gene single-nucleotide polymorphism (SNP) rs1360780 have an increased susceptibility to adverse effects of experimental stress. We therefore tested the hypothesis of an interaction of childhood abuse with rs1360780 in predicting adult depression. In all, 2157 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and Childhood Trauma Questionnaire. The DSM-IV diagnosis of major depressive disorder (MDD) was assessed by interview. Genotypes of rs1360780 were taken from the Affymetrix Human SNP Array 6.0. Significant interaction (p ¼ 0.006) of physical abuse with the TT genotype of rs1360780 was found increasing the BDI-II score to 17.4 (95% confidence interval (CI) ¼ 12.0-22.9) compared with 10.0 (8.2-11.7) in exposed CC/CT carriers. Likewise, the adjusted odds ratio for MDD in exposed TT carriers was 8.2 (95% CI ¼ 1.9-35.0) compared with 1.3 (0.8-2.3) in exposed subjects with CC/CT genotypes. Relative excess risk due to interaction (RERI) analyses confirmed a significant additive interaction effect (RERI ¼ 6.8; po0.05). In explorative analyses, the most severe degree of sexual and emotional abuse also yielded significant interaction effects (po0.05). This study revealed interactions between physical abuse and rs1360780 of the FKBP5 gene, confirming its role in the individual susceptibility to depression. Given the large effect sizes, rs1360780 could be included into prediction models for depression in individuals exposed to childhood abuse.

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

“…Similarly, elevated glucocorticoid levels have been associated with larger amygdala volumes (Buss et al 2012;Lupien et al 2011). Considering a heightened amygdala response and a larger volume as possible endophenotypes for stress-related disorders, the present findings are in line with previous reports suggesting an important role of the FKBP5 T allele in mood disorders (Appel et al 2011;Binder et al 2004;Lavebratt et al 2010;Lekman et al 2008;Zobel et al 2010) and PTSD (Binder et al 2008).…”

“…In line with this, rs1360780 has been associated with psychopathology such as mood disorders (Binder et al 2004;Lavebratt et al 2010;Lekman et al 2008;Zobel et al 2010) and suicidality (Brent et al 2010). Moreover, this SNP has been shown to interact with childhood abuse in predicting PTSD symptoms (Binder et al 2008) and susceptibility to depression (Appel et al 2011), with an increased risk in the TT genotype following childhood abuse.…”

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

“…Taken together with previous reports, it appears that hippocampal sensitivity to stressors and subsequent cortisol fluctuations leads to decreased hippocampal functioning and possibly reduced hippocampal volume. All these findings, along with a number of other recent observations (Xie et al, 2010;Zimmermann et al, 2011;Appel et al, 2011;Buchmann et al, 2014), suggest a model in which the FKBP5 genotype is associated with enhanced intermediate neural and behavioral phenotypes that may underlie increased risk for PTSD and other stress-related psychiatric illnesses following trauma exposure.…”

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing

“…Lifetime diagnoses were assigned according to diagnostic hierarchy rules and exclusion criteria as stated in the DSM-IV-TR. Further details on sampling, assessment procedures and quality assurance are reported in detail elsewhere 40 .…”

“…The sample comprised 160 individuals reporting panic attacks (female=103, male=57; mean age 51.4±12.0; of those, 74 met diagnostic criteria of PD with or without agoraphobia [female=54, male=20; mean age 50.9±11.1]) and their sex-matched healthy controls (n=160; female=101, male=59; mean age 51.4±12.0). All participants were drawn from a follow-up examination of 6,267 participants of the epidemiological Study of Health in Pomerania (SHiP), reported in detail elsewhere 40,41 . Criteria of a panic attack or confirmed PD were assessed using a standardized computerassisted personal version of the Munich Composite International Diagnostic Interview (M-CIDI; 42 ).…”