Interaction of FKBP5, a Stress-Related Gene, with Childhood Trauma Increases the Risk for Attempting Suicide

Abstract

Childhood trauma is associated with hypothalamic-pituitary-adrenal axis (HPA) dysregulation and is a known risk factor for suicidal behavior. In this study we sought to determine whether the impact of childhood trauma on suicide risk might be modified by FKBP5, an HPA axis regulating gene. Sixteen FKBP5 haplotype tagging SNPs were genotyped in a sample of African Americans: 398 treatment seeking patients with substance dependence (90% men; 120 suicide attempters) and 432 non-substance dependent individuals (40% men; 21 suicide attempters). In all, a total of 474 participants (112 suicide attempters) also completed the Childhood Trauma Questionnaire (CTQ). Primary haplotype analyses were conducted with the four SNPs implicated in earlier studies: rs3800373, rs9296158, rs1360780 and rs9470080. We found that childhood trauma was associated with suicide attempt (p < 0.0001). Although there was no main effect of the two major yin yang haplotypes in the four SNP haplotype block, there was a haplotype influence on suicide risk (p = 0.006) only in individuals exposed to high levels of childhood trauma. In this group, 51% with two copies of the risk haplotype, 36% with one copy, and 20% with no copies had attempted suicide. The total logistic regression model accounted for 13% of the variance in attempted suicide. Analyses of the 16 SNPs showed significant main effects on suicide attempt of rs3777747, rs4713902 and rs9470080 and interactive effects of rs3800373, rs9296158, and rs1360780 with CTQ score on suicide attempt. These data suggest that childhood trauma and variants of the FKBP5 gene may interact to increase the risk for attempting suicide.

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

“…The interaction between SNPs of the FKBP5 gene (including rs1360780) and childhood adversity in PTSD was confirmed in African Americans but not in European Americans (Xie et al, 2010). A further study found interactions between SNPs of the FKBP5 gene (including rs1360780) and childhood trauma in adult suicide attempts; however, in this study, the common risk allele was protective (Roy et al, 2010). As some studies have suggested that early life stress precedes the HPA axis hyperactivity observed in major depressive disorder (MDD) (Heim and Nemeroff, 2001;Carpenter et al, 2004), an interaction between variations within the FKBP5 gene and childhood abuse could be of relevance in adult depression too.…”

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

“…In the subsample of European Americans, the significant association between haplotype GAACTT and alcohol withdrawal severity also disappeared after covariate adjustment (Supplementary Table 4). When we examined haplotypes composed of rs3800373, rs9296158, rs1360780, and rs9470080 (see Supplementary Figure 1 for LD structure of these four SNPs), which have been previously reported to be potentially functional and associated with several measures of psychopathology (Binder et al, 2004(Binder et al, , 2008Ising et al, 2008;Roy et al, 2010;Xie et al, 2010), we found that haplotype GATT and the complementary TGCC were positively and negatively associated with withdrawal severity, respectively (Supplementary Table 5); however, these results also did not remain after adjustment for covariates. These findings suggest that haplotypes consisting of minor alleles are linked to a lower severity of alcohol withdrawal.…”

“…In addition, the minor alleles of rs9470080 and rs1360780 are associated with total cortisol secretion during the day expressed as the AUC (cortisol AUC ) (Velders et al, 2011). Finally, a haplotype of the above-listed SNPs has been associated with suicidal attempts (Roy et al, 2010) or aggressive behavior (Bevilacqua et al, 2012) among individuals with childhood trauma.…”

“…In this study, the FKBP5 SNPs were selected based on those that have been implicated in a previous study (Roy et al, 2010) and could be captured from the available genetic information in the existing Illumina data set for FKBP5, including rs3800373, rs9296158, rs3777747, rs9380524, and rs9470080. An additional SNP not included in the Illumina OmniExpress array, rs1360780, was also genotyped as the functionality of this variant in the negative feedback of GR regulation has been investigated and characterized (Binder et al, 2004;Ising et al, 2008;Roy et al, 2010;Xie et al, 2010;Zannas and Binder, 2014). Rs1360780 was genotyped using the assay-on-demand (assay ID: C___8852038_10 ) from Applied Biosystems (Foster City, CA).…”

“…Accordingly, variation in the FKBP5 gene has been associated with reduced dexamethasone suppression (Binder et al, 2008), incomplete normalization of stress-elicited cortisol secretion (Ising et al, 2008), and response to antidepressants and recurrence of depressive episodes (Binder et al, 2004). FKBP5 variation has also been shown to interact with childhood trauma exposure to increase the risk for posttraumatic stress disorder (PTSD) (Binder et al, 2008;Xie et al, 2010) as well as suicidal behavior (Roy et al, 2010). Furthermore, genotype-specific FKBP5 DNA methylation may mediate these genechildhood trauma interactions (Klengel et al, 2013).…”