Autor:innen:
Thomas Leon Kremer, Mannheim (Germany)
Urs Braun, Mannheim (Germany)
Junfang Chen, Mannheim (Germany)
Anais Harneit, Mannheim (Germany)
Kristina Schwarz, Mannheim (Germany)
Janina Schweiger, Mannheim (Germany)
Markus Reichert, Mannheim (Germany)
Emanuel Schwarz, Mannheim (Germany)
Andreas Meyer-Lindenberg, Mannheim (Germany)
Heike Tost, Mannheim (Germany)
Integration of multi-modal psychiatric risk mechanisms is a major goal of modern translational neuroscience. Here we intergrate structural variation of stress processing brain circuits, explicitly the anterior cingulate cortex (ACC), with the epigenetic signature of FKBP5, a regulator of the HPA-axis. Both have been shown to be mediating factors of adverse gene-environment interactions on psychiatric risk. Two specific DNA-Methylation(DNAm) loci in FKBP5 have recently been identified as being particularly relevant for its epigenetic regulation and were chosen as loci of interest.
427 healthy caucasian subjects underwent T1-MPRAGE MRI-Scans and Illumina EPIC array DNAm profiling on whole-blood samples. Imaging data was preprocessed using the CAT12 toolbox (in SPM12) following standard procedures. Epigenetic data was residualized for sex, age, cell composition, smoking and the first 10 PC. DNAm of two specific loci of interest were averaged. Two linear regressions were conducted on grey matter volume with FKBP5 DNAm [n=427] and the STAI-T [n=224] as predictors. ROI mask comprised ACC, medial prefrontal cortex, hippocampus and amygdala. A mediation model was applied to test for an indirect effect of FKBP5 DNAm on STAI-T scores mediated by sgACC-volume using the PROCESS-macro in SPSS.
FKBP5 DNAm was significantly associated with grey matter volume in OFC (T=4.51, p=.007 FWE-corrected in ROI) and the sgACC (T=4.43, p=.009 FWE-corrected in ROI). Trait anxiety was negatively associated with sgACC volume (T=-3.79, p=.073 FWE-corrected in ROI). The mediation-analysis showed a significant indirect effect of FKBP5 DNAm on trait anxiety, mediated by sgACC volume (CI=[-22.74, -1.23]), in absence of direct effect.
We demonstrate that structural variation in brain circuits underlying neural stress processing relates to DNAm of key loci in FKBP5 and an established risk marker for mental illness and mediates the association between epigenetic and psychological risk.