FKBP5 haplotypes and PTSD modulate the resting-state brain activity in Han Chinese adults who lost their only child

Rongfeng Qi,Zhihong Cao,Paul M Thompson,Li Zhang,Yifei Weng,Yan Yin,Wesley Surento,Neda Jahanshad,Qiang Xu,Guang Ming Lu,Yifeng Luo,Lingjiang Li

doi:10.1038/s41398-020-0770-5

Abstract

The stress-related gene FKBP5 has been related to dysregulated glucocorticoid receptor (GR) signaling, showing increased GR sensitivity in trauma-exposed subjects with post-traumatic stress disorder (PTSD) but not in those without PTSD. However, the neural mechanism underlying the effects of FKBP5 remains poorly understood. Two hundred and thirty-seven Han Chinese adults who had lost their only child were included. Four FKBP5 single nucleotide polymorphisms (rs3800373, rs9296158, rs1360780, and rs9470080) were genotyped. All 179 participants were successfully divided into three FKBP5 diplotype subgroups according to two major FKBP5 H1 and H2 yin yang haplotypes. Brain average spectral power was compared using a two-way (PTSD diagnosis and FKBP5 diplotypes) analysis of covariance within four separate frequency bands (slow-5, slow-4, slow-3, and slow-2). Adults with PTSD showed lower spectral power in bilateral parietal lobules in slow-4 and in left inferior frontal gyrus (IFG) in slow-5. There was significant FKBP5 diplotype main effect in anterior cingulate cortex (ACC) in slow-4 (H1/H1 higher than other two subgroups), and in precentral/postcentral gyri and middle cingulate cortex (MCC) in slow-3 (H2/H2 higher than other two subgroups). Also, there was a significant diagnosis × FKBP5 diplotype interaction effect in right parietal lobule in slow-3. These findings suggest that adults with PTSD have lower low-frequency power in executive control network regions. Lower power in ACC and greater power in the motor/sensory areas in FKBP5 high-risk diplotype group suggest a disturbance of emotional processing and hypervigilance/sensitization to threatening stimuli. The interaction effect of diagnosis × FKBP5 in parietal lobule may contribute to PTSD development.

Highlights

Post-traumatic stress disorder (PTSD) is characterized by dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis after exposure to traumatic events, displayed as enhanced negative-feedback inhibition of the HPA axis[1,2]
We aimed to examine the modulatory effects of FK506-binding protein 5 (FKBP5) H1 and H2 yin yang haplotypes on resting state brain function using resting-state fMRI in trauma-exposed subjects with and without PTSD
All 179 adults (49 with PTSD and 130 without PTSD) who carried homozygote and heterozygote combinations of the H1 and H2 haplotypes were included in the final FKBP5 diplotypes based neuroimaging analyses (Table 1 and Supplementary Table 3)

Summary

Introduction

Post-traumatic stress disorder (PTSD) is characterized by dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis after exposure to traumatic events, displayed as enhanced negative-feedback inhibition of the HPA axis[1,2]. One typical clinical feature of this abnormality in PTSD is an exaggerated suppression of cortisol in response to dexamethasone administration and the enhanced sensitivity of glucocorticoid receptors (GR)[3,4]. Only a minority of trauma-exposed individuals will eventually develop PTSD5, and the increased GR sensitivity following stress happens only in PTSD but not in non-PTSD subjects[3,4]. The underlying mechanisms of the association between PTSD development and GR sensitivity remain poorly understood. Genetic factors that regulate GR signaling influence the individual differences in the HPA axis response to stress[6,7]. In the absence of cortisol, FKBP5 binds to the GR

Objectives

Methods

Results

Discussion

Conclusion