Epigenetische Modifikation des FKBP5-Gens und Hirnstruktur

Die vorliegende Arbeit untersucht den Einfluss epigenetischer Modifikation des FKBP5-Gens auf Hirnstruktur im Kontext von Depressionsrisiko und Kindheitstraumata. Betrachtet wurde ein Risikosample bestehend aus N = 62 Probandinnen. Die Stichprobe schloss Gesunde ohne Risiko, Gesunde mit genetischem...

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Bibliographic Details
Main Author: Fröhlich, Lena
Contributors: Nenadić, Igor (Prof. Dr. med) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2022
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Table of Contents: In this study we examined the influence of epigenetic modification of the FKBP5 gene on brain structure in context of depression risk and childhood trauma. To investigate associations of the FKBP5 gene methylation and brain structure the present study obtained epigenetic, clinical and structural data from 62 healthy females including participants with genetic risk, with environmental risk and without risk. FKBP5 gene methylation was obtained from whole blood using the Illumina Infinium MethylationEPIC BeadChip. Childhood adversity was assessed by the Childhood Trauma Questionnaire (CTQ). Subjects underwent a magnetic resonance imaging protocol, which included structural measures of voxel-based morphometry and diffusion tensor imaging. Next to obtaining gray matter volume from T1-weighted images, fractional anisotropy was applied to diffusion weighted MRI scans to emphasize and evaluate the integrity of white matter fiber tracts.Although the examination did not reveal any correlation between epigenetic changes of the FKBP5 gene and childhood trauma, the individual association of the FKBP5 gene methylation and the CTQ score with brain structure led to multiple significant findings. Our analysis revealed that FKBP5 gene methylation was linked to gray matter volume in the right occipital gyrus, as well as fractional anisotropy in the left and right cingulum. These alterations of white matter integrity included cingulate fiber pathways connected to the left hippocampus. Replicating and extending previous findings voxel-based morphometry confirmed that childhood maltreatment was associated with reduced hippocampal volumes in healthy adults, while TBSS revealed a trauma-associated FA-Reduction over large parts of the brain. Particular attention was paid to the superior longitudinal fasciculus, a fiber pathway involved in the transmission of sensory information from occipital and temporal brain regions to the prefrontal cortex. Fractional anisotropy of the superior longitudinal fasciculus was both associated with FKBP5 gene methylation and the CTQ score.Overall, our findings suggest that trauma associated alterations of gray matter volume and white fiber integrity might be mediated by epigenetic modifications and modulate risk of depression. To verify and validate our results in limbic and sensory systems, future studies need to take genetic data and individual effects by specific types of maltreatment into account. While our results demonstrate that epigenetic imaging contributes to assess the role of epigenetics in the etiology of psychiatric disorders, further interpretation of recent findings are limited by methodological heterogeneity as well as unknown disturbance variables and interactions. Therefore, future studies should focus on attaining a deeper understanding of underlying molecular genetic mechanisms and strive for a harmonization of acquisition and analysis protocols.