Dataset Information

Effect of the interaction between childhood abuse and rs1360780 of the FKBP5 gene on gray matter volume in a general population sample.

ABSTRACT: OBJECTIVE:The FKBP5 gene codes for a co-chaperone that regulates glucocorticoid receptor sensitivity and thereby impacts the reactivity of the hypothalamic-pituitary-adrenal (HPA)-axis. Evidence suggested that subjects exposed to childhood abuse and carrying the TT genotype of the FKBP5 gene single nucleotide polymorphism (SNP) rs1360780 have an increased susceptibility to stress-related disorders. METHOD:The hypothesis that abused TT genotype carriers show changes in gray matter (GM) volumes in affect-processing brain areas was investigated. About 1,826 Caucasian subjects (age???65 years) from the general population [Study of Health in Pomerania (SHIP)] in Germany were investigated. The interaction between rs1360780 and child abuse (Childhood Trauma Questionnaire) and its effect on GM were analyzed. RESULTS:Voxel-based whole-brain interaction analysis revealed three large clusters (FWE-corrected) of reduced GM volumes comprising the bilateral insula, the superior and middle temporal gyrus, the bilateral hippocampus, the right amygdala, and the bilateral anterior cingulate cortex in abused TT carriers. These results were not confounded by major depressive disorders. In region of interest analyses, highly significant volume reductions in the right hippocampus/parahippocampus, the bilateral anterior and middle cingulate cortex, the insula, and the amygdala were confirmed in abused TT carriers compared with abused CT/CC carriers. CONCLUSION:The results supported the hypothesis that the FKBP5 rs1360780 TT genotype predisposes subjects who have experienced childhood abuse to widespread structural brain changes in the subcortical and cortical emotion-processing brain areas. Those brain changes might contribute to an increased vulnerability of stress-related disorders in TT genotype carriers.

SUBMITTER: Grabe HJ

PROVIDER: S-EPMC6867563 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Effect of the interaction between childhood abuse and rs1360780 of the FKBP5 gene on gray matter volume in a general population sample.

Grabe Hans Jörgen HJ Wittfeld Katharina K Van der Auwera Sandra S Janowitz Deborah D Hegenscheid Katrin K Habes Mohamad M Homuth Georg G Barnow Sven S John Ulrich U Nauck Matthias M Völzke Henry H Meyer zu Schwabedissen Henriette H Freyberger Harald Jürgen HJ Hosten Norbert N

Human brain mapping 20160127 4

<h4>Objective</h4>The FKBP5 gene codes for a co-chaperone that regulates glucocorticoid receptor sensitivity and thereby impacts the reactivity of the hypothalamic-pituitary-adrenal (HPA)-axis. Evidence suggested that subjects exposed to childhood abuse and carrying the TT genotype of the FKBP5 gene single nucleotide polymorphism (SNP) rs1360780 have an increased susceptibility to stress-related disorders.<h4>Method</h4>The hypothesis that abused TT genotype carriers show changes in gray matter ...[more]

PMID: 26813705

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Project description: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.

Project description:BackgroundChildhood trauma is one of the most extensively studied and well-supported environmental risk factors for the development of mental health problems. The human tryptophan hydroxylase 2 (TPH2) gene is one of the most promising candidate genes in numerous psychiatric disorders. However, it is now widely acknowledged that neither genetic variation nor environmental exposure alone can fully explain all the phenotypic variance observed in psychiatric disorders. Therefore, it is necessary to consider the interaction between the two factors in psychiatric research.MethodsWe enrolled a sizable nonclinical cohort of 786 young, healthy adults who underwent structural MRI scans and completed genotyping, the Childhood Trauma Questionnaire (CTQ) and behavioural scores. We identified the interaction between childhood trauma and the TPH2 rs7305115 gene polymorphism in the gray matter volume (GMV) of specific brain subregions and the behaviour in our sample using a multiple linear regression framework. We utilized mediation effect analysis to identify environment /gene-brain-behaviour relationships.ResultsWe found that childhood trauma and TPH2 rs7305115 interacted in both behaviour and the GMV of brain subregions. Our findings indicated that the GMV of the right posterior parietal thalamus served as a significant mediator supporting relationship between childhood trauma (measured by CTQ score) and anxiety scores in our study population, and the process was partly modulated by the TPH2 rs7305115 gene polymorphism. Moreover, we found only a main effect of childhood trauma in the GMV of the right parahippocampal gyrus area, supporting the relationship between childhood trauma and anxiety scores as a significant mediator.ConclusionsOur findings suggest that early-life trauma may have a specific and long-term structural effect on brain GMV, potentially leading to altered cognitive and emotional processes involving the parahippocampal gyrus and thalamus that may also be modulated by the TPH2 gene polymorphism. This finding highlights the importance of considering genetic factors when examining the impact of early-life experiences on brain structure and function. Gene‒environment studies can be regarded as a powerful objective supplement for targeted therapy, early diagnosis and treatment evaluation in the future.

Project description:BackgroundDespite decades of research, there is continued uncertainty regarding whether autism is associated with a specific profile of gray matter (GM) structure. This inconsistency may stem from the widespread use of voxel-based morphometry (VBM) methods that combine indices of GM density and GM volume. If GM density or volume, but not both, prove different in autism, the traditional VBM approach of combining the two indices may obscure the difference. The present study measures GM density and volume separately to examine whether autism is associated with alterations in GM volume, density, or both.MethodsDifferences in MRI-based GM density and volume were examined in 6-25 year-olds with a diagnosis of autism spectrum disorder (n = 213, 80.8% male, IQ 47-154) and a typically developing (TD) sample (n = 190, 71.6% male, IQ 67-155). High-resolution T1-weighted anatomical images were collected on a single MRI scanner. Regional density and volume were estimated via whole-brain parcellation comprised of 1625 parcels. Parcel-wise analyses were conducted using generalized additive models while controlling the false discovery rate (FDR, q < 0.05). Volume differences in the 68-region Desikan-Killiany atlas derived from Freesurfer were also examined, to establish the generalizability of findings across methods.ResultsNo density differences were observed between the autistic and TD groups, either in individual parcels or whole brain mean density. Increased volume was observed in autism compared to the TD group when controlling for Age, Sex, and IQ, both at the level of the whole brain (total volume) and in 45 parcels (2.8% of total parcels). Parcels with greater volume included inferior, middle, and superior temporal gyrus, inferior and superior frontal gyrus, precuneus, and fusiform gyrus. Converging evidence from a standard Freesurfer pipeline also identified greater volume in a number of overlapping regions.LimitationsThe method for determining "density" is not a direct measure of neuronal density, and this study cannot reveal underlying cellular differences. While this study represents possibly the largest single-site sample of its kind, it is underpowered to detect very small differences.ConclusionsThese results provide compelling evidence that autism is associated with regional GM volumetric differences, which are more prominent than density differences. This underscores the importance of examining volume and density separately, and suggests that direct measures of volume (e.g. region-of-interest or tensor-based morphometry approaches) may be more sensitive to autism-relevant differences in neuroanatomy than concentration/density-based approaches.

Project description:ObjectiveAlthough lower brain volume has been routinely observed in individuals with substance dependence compared with nondependent control subjects, the brain regions exhibiting lower volume have not been consistent across studies. In addition, it is not clear whether a common set of regions are involved in substance dependence regardless of the substance used or whether some brain volume effects are substance specific. Resolution of these issues may contribute to the identification of clinically relevant imaging biomarkers. Using pooled data from 14 countries, the authors sought to identify general and substance-specific associations between dependence and regional brain volumes.MethodBrain structure was examined in a mega-analysis of previously published data pooled from 23 laboratories, including 3,240 individuals, 2,140 of whom had substance dependence on one of five substances: alcohol, nicotine, cocaine, methamphetamine, or cannabis. Subcortical volume and cortical thickness in regions defined by FreeSurfer were compared with nondependent control subjects when all sampled substance categories were combined, as well as separately, while controlling for age, sex, imaging site, and total intracranial volume. Because of extensive associations with alcohol dependence, a secondary contrast was also performed for dependence on all substances except alcohol. An optimized split-half strategy was used to assess the reliability of the findings.ResultsLower volume or thickness was observed in many brain regions in individuals with substance dependence. The greatest effects were associated with alcohol use disorder. A set of affected regions related to dependence in general, regardless of the substance, included the insula and the medial orbitofrontal cortex. Furthermore, a support vector machine multivariate classification of regional brain volumes successfully classified individuals with substance dependence on alcohol or nicotine relative to nondependent control subjects.ConclusionsThe results indicate that dependence on a range of different substances shares a common neural substrate and that differential patterns of regional volume could serve as useful biomarkers of dependence on alcohol and nicotine.

Dataset Information

Effect of the interaction between childhood abuse and rs1360780 of the FKBP5 gene on gray matter volume in a general population sample.

Publications

Effect of the interaction between childhood abuse and rs1360780 of the FKBP5 gene on gray matter volume in a general population sample.

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