FKBP5 DNA methylation does not mediate the association between childhood maltreatment and depression symptom severity in the Detroit Neighborhood Health Study

Abstract

Exposure to childhood maltreatment increases the risk of developing mental illness later in life. Childhood maltreatment and depression have both been associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis-a key regulator of the body's stress response. Additionally, HPA axis dysregulation has been implicated in the etiology of a range of mental illnesses. A substantial body of work has shown history of childhood maltreatment alters DNA methylation levels within key HPA axis genes. We therefore investigated whether one of these key genes, FKBP5 mediates the relationship between childhood maltreatment and depression, and assessed FKBP5 DNA methylation and gene expression within 112 adults from the Detroit Neighborhood Health Study (DNHS). DNA methylation was assessed in 4 regions, including the upstream promoter, downstream promoter, and two glucocorticoid response elements (GREs) via pyrosequencing using whole blood derived DNA; Taqman assays measured relative RNA expression from leukocytes. Mediation analyses were conducted using sequential linear regression. Childhood maltreatment was significantly associated with depression symptom severity (FDR < 0.006), but was not a significant predictor of DNA methylation in any of the four loci examined. FKBP5 showed elevated expression levels in participants with vs. without a history of depression (p < 0.001); no significant difference in gene expression levels was observed in relation to childhood maltreatment (p > 0.05). Our results suggest DNA methylation does not mediate the childhood maltreatment-depression association in the DNHS.

Keywords: Childhood maltreatment; Epigenetics; Gene expression; Major depressive disorder; Mediation.

Figure 1

Schematic showing the four regions examined within the study indicated by shading upstream promoter (CHR6:35,656,797–35,656,920), downstream promoter (CHR6:35,655,829–35,655,843), and introns 2 (CHR6:35,558,310–35,558,785) and 7 (CHR6:35,607,754 −35,608,049). All coordinates provided are from the UCSC Genome Browser Build 2009/hg19. The CpG sites examined within this study are indicated in uppercase, bold font, and green text. Lower case letters indicate intronic regions. The transcription factor binding site is indicated by underlined sequence.

Figure 2

Schematic showing the mediation framework for our analysis. Letters indicate the order the regressions were tested. Note analysis “d” was only tested for Intron 7.

Figure 3

Summary of the mediation analyses for each region of FKBP5 tested upstream promoter (a), downstream promoter (b), intron 2 (c), and Intron 7 (d). Significant results are indicated by bold black text and denoted unadjusted p-value and FDR. Non-significant results are denoted by gray text and “N.S” for non-significant.

Figure 4

FKBP5 gene expression levels among individuals with (n=35) vs. without (n=36) exposure to childhood maltreatment and participants with (n=25) vs. without (n=46) lifetime major depressive disorder history. T-tests showed a significant (p<0.001) increase in gene expression levels among major depressive disorder cases compared to controls. Error bars represent standard error and asterisk denotes significant p<0.05.