Single-Nucleotide Polymorphism of the FKBP5 Gene and Childhood Maltreatment as Predictors of Structural Changes in Brain Areas Involved in Emotional Processing in Depression

Abstract

The gene expressing the FK506 binding protein 51 (FKBP5) is involved in the regulation of glucocorticoid receptor sensitivity. The rs1360780 SNP in this gene (T allele vs C homozygous) has been found to be associated with major depressive disorder (MDD). The aim of our study was to investigate whether this polymorphism might be associated with altered brain structure and function in a cohort of 40 patients with MDD and 43 healthy controls. A functional magnetic resonance imaging (fMRI) emotional attention task was employed. Diffusion tensor imaging (DTI) was also conducted, extracting mean diffusivity (MD) and fractional anisotropy (FA) from brain areas that showed functional differences between patients expressing the two alleles of the rs1360780 SNP. Finally, the effect of the interaction of childhood adversity as measured by the Childhood trauma Questionnaire (CTQ) and rs1360780 allele status was analyzed in relation to DTI measures using a general linear model. All results presented are family-wise error (FWE) corrected. Functional interactions were found between genotype and diagnosis (po0.01). Patients carrying the high-risk allele, compared with patients not carrying it, showed reduced activity in the rolandic operculum, Heschl gyrus, insula, parahippocampal gyrus, posterior cingulate cortex, inferior frontal gyrus (po0.05 for all measures); and increased MD and reduced FA measures in many of these regions (po0.05). An interaction between CTQ scores and allele status was associated with DTI changes in the insula, rolandic operculum, and inferior frontal gyrus. Here, the presence of both the high-risk allele and higher CTQ scores was associated with higher MD and lower FA values (po0.05). In conclusion, MDD patients expressing the T allele of rs1360780, compared with C homozygous patients, exhibit functional and structural differences in areas involved in emotional perception and inhibition. The interaction between the T allele and childhood maltreatment explained our structural findings in these regions, suggesting that their altered maturation and function might be influenced by early chronic stress in the presence of this genetic trait.

FKBP5 interacts with maltreatment in children with extreme, pervasive, and persistent aggression

“…Our finding, however, was that of gene-environment interaction, and thus adds to the growing literature supporting the role of FKBP5 in susceptibility to maltreatment and childhood trauma. While most studies implicating FKBP5 in vulnerability to maltreatment were conducted in adults (Bevilacqua et al, 2012;Fani et al, 2014;Buchmann et al, 2014;Tozzi et al, 2015), the present study suggests that this susceptibility may emerge early in life. The FKBP5 gene is differentially methylated in maltreated as opposed to non-maltreated children (Weder et al, 2014), this methylation is allele-specific (Klengel et al, 2013) which suggests that the underlying mechanism of this gene-environment interaction is epigenetic.…”

Neuroimaging genomic studies in major depressive disorder: A systematic review

“…In this systematic review, neuroimaging alteration in MDD was found to be associated with FK506‐binding protein 51 (FKBP5) and corticotropin‐releasing hormone receptor 1 (CRHR1) genes . The dysfunction of glucocorticoid receptor and endogenous glucocorticoid levels impair the HPA axis feedback inhibition in depressed patients.…”

“…70,71 MDD patients with an MAOA H-allele showed significantly lower amygdalaprefrontal connectivity, 72 but not in those with 5-HTTLPR genetic variants. 70,73 Other studies have reported significant genotype-diagnosis interaction effects on emotional regulation systems for FKBP5, 74 CACNA1C, 75 CRHR1, 64 and BICCI 39 genes. The remaining studies showed decreased activation of the striatum with a PCLO risk allele, decreased activation of right frontal middle gyrus in a 5-HT2A T-allele, or decreased connectivity of amygdala-prefrontal circuitry with the MAOA H-allele.…”

“…In this systematic review, neuroimaging alteration in MDD was found to be associated with FK506-binding protein 51 (FKBP5) and corticotropin-releasing hormone receptor 1 (CRHR1) genes. 64,74 The dysfunction of glucocorticoid receptor and endogenous glucocorticoid levels impair the HPA axis feedback inhibition in depressed patients. Abnormal glucocorticoid levels can inhibit neural proliferation and encourage dendritic atrophy, which in turn causes brain structural and functional alterations.…”

Serotonin and early life stress interact to shape brain architecture and anxious avoidant behavior – a TPH2 imaging genetics approach

“…Initial studies that combined a candidate gene approach with neuroimaging reported that specific single-nucleotide polymorphisms (SNPs) of genes associated with neuroplasticity and stress reactivity, including brain derived neurotrophic factor, glucocorticoid and oxytocin receptor sensitivity, confer greater sensitivity to the detrimental impact of ELS, e.g. pronounced reductions of limbic volumes (Dannlowski et al 2016;Tozzi et al 2016;van Velzen et al 2016). Interestingly, two initial studies reported that specific allelic combinations associated with differences in central dopamine and serotonergic functioning exhibited ELS-associated changes in hippocampal and amygdala activation that may reflect improved threat learning and implicit emotion regulation following early aversive experiences (Hermann et al 2012;van Rooij et al 2017).…”