Introduction: Compared with healthy controls, women with Cushings syndrome (CS) in long-term remission have reduced functional brain responses during episodic and working memory testing and decreased overall levels of DNA methylation in blood cells. Here, we sought to test the hypothesis that functional brain responses in the prefrontal cortex and hippocampus are related to epigenetic changes in subjects with CS in long-term remission.
Methods: In this pilot study, 10 women with CS in remission were included. The mean (SD) age was 40±11 yrs and the median (IQR) duration of remission was 9.6 (515) yrs. Six patients had Cushings disease and 4 had a cortisol-producing adrenal adenoma. Functional brain responses were studied with functional magnetic resonance imaging (fMRI) during episodic- and working-memory tasks. DNA was isolated from whole blood and DNA methylation was analysed using the Illumina Infinium HumanMethylation450K BeadChip. In a previous analysis, 461 differentially methylated regions, containing 3,903 probes, were identified in patients with CS in remission compared to healthy controls. Correlations between individual probes and fMRI data were analysed in R, and a false discovery rate (FDR) adjusted P (q-value) < 0.2 was considered significant.
Results: Using the predetermined q-value cut off, significant correlations were found between probes and functional brain responses in both right and left hippocampi (n=592 and 967 unique probes, respectively). Correlations were also found for right posterior (n=1145 unique probes), left anterior (n=900 probes) and left posterior (n=1.198 probes) hippocampi. Gene ontology analyses revealed that probes correlating to fMRI responses mapped to genes associated with long-term memory function and regulation of synaptic plasticity, to mention some. Three probes in COL11A2, DAGLB and TFDP1 genes, previously associated with psychopathology in CS, were also strongly correlated with functional brain responses. Furthermore, one gene with several significantly correlated probes was RNF39, a gene previously suggested to be a mediator of the effect of stress on central fear and stress circuitries in the brain.
Conclusions: In women with CS in long-term remission, DNA methylation is correlated with functional brain responses during memory encoding. Some differently methylated genes associated with functional brain response have previously been associated with psychopathology in CS and one, RNF39, is suggested to be a susceptibility locus for post-traumatic stress disorder.
18 - 21 May 2019
European Society of Endocrinology