Rs1360780 of the FKBP5 gene modulates the association between maternal acceptance and regional gray matter volume in the thalamus in children and adolescents.

Hiroaki Tomita,Ryuta Kawashima,Atsushi Sekiguchi,Izumi Matsudaira,Kentaro Oba,Yasuyuki Taki,Sarah Whittle,Hikaru Takeuchi

doi:10.1371/journal.pone.0221768

Abstract

Investigating the effects of gene–environment interactions (G × E) with regard to brain structure may help to elucidate the putative mechanisms associated with psychiatric risk. rs1360780 (C/T) is a functional single-nucleotide polymorphism (SNP) in the gene encoding FK506–binding protein 5 (FKBP5), which is involved in the regulation of the hypothalamic–pituitary–adrenal (HPA) axis stress responses. The minor (T) allele of FKBP5 is considered a risk allele for stress-related disorders, due to the overproduction of FKBP5, which results in impaired communication of stress signals with the HPA axis. Previous studies have reported that interactions between childhood maltreatment and the rs1360780 genotype affect structures in subcortical areas of the brain. However, it is unclear how this SNP modulates the association between non-adverse environments and brain structure. In this study, we examined the interactive effect of the rs1360780 genotype and maternal acceptance on the regional gray matter volume (rGMV) in 202 Japanese children. Maternal acceptance was assessed using a Japanese psychological questionnaire for mothers. Whole-brain multiple regression analysis using voxel-based morphometry showed a significant positive association between maternal acceptance and rGMV in the left thalamus of T-allele carriers, while a significant negative association was found in C/C homozygotes. Post-hoc analysis revealed that at or below the 70th percentiles of maternal acceptance, the T-allele carriers had a reduced thalamic rGMV compared with that of C/C homozygotes. Thus, our investigation indicated that the effect of the maternal acceptance level on brain development was different, depending on the rs1360780 genotype. Importantly, we found that the differences in brain structure between the T-allele carriers and C/C homozygotes at low to moderate levels of maternal acceptance, which is not equivalent to maltreatment. The present study contributes to the G × E research by highlighting the necessity to investigate the role of non-adverse environmental factors.

Highlights

Gene–environment interactions (G × E) are defined as different effects of the environment on human behaviors, depending on the genotype, and vice versa
To the best of our knowledge, this is the first study to demonstrate the interactive effect of the FK506-binding protein 5 (FKBP5) rs1360780 genotype and a non-adverse environmental factor on brain structure
We found a significant positive association between maternal acceptance and regional gray matter volume (rGMV) in the thalamus of T-allele carriers

Summary

Introduction

Gene–environment interactions (G × E) are defined as different effects of the environment on human behaviors, depending on the genotype, and vice versa. Numerous studies have demonstrated that the rs1360780 (C/T) single–nucleotide polymorphism (SNP) in the gene encoding FK506-binding protein 5 (FKBP5) modulates the association between early-life adversity and brain structure or function [5,6,7,8]. It has been shown that early-life stress induces demethylation of a functional GR element within intron 7 of FKBP5, in Tallele carriers [10]. This demethylation increases the FKBP5 overexpression following GR activation, resulting in further suppression of negative feedback [10]. The affected brain areas were inconsistent among various studies, neuroimaging [5,6,7,8] and epigenetic [10] evidence provides robust support for the interaction between FKBP5 rs1360780 and early-life adversity with respect to brain structure

Methods

Results

Conclusion