Reduced DNA methylation and psychopathology following endogenous hypercortisolism \u2013 a genome-wide study

Camilla A M Glad,Johanna C Andersson-Assarsson,Ragnhildur Bergthorsdottir,Oskar Ragnarsson,Peter Berglund,Gudmundur Johannsson

doi:10.1038/srep44445

Abstract

Patients with Cushing’s Syndrome (CS) in remission were used as a model to test the hypothesis that long-standing excessive cortisol exposure induces changes in DNA methylation that are associated with persisting neuropsychological consequences. Genome-wide DNA methylation was assessed in 48 women with CS in long-term remission (cases) and 16 controls matched for age, gender and education. The Fatigue impact scale and the comprehensive psychopathological rating scale were used to evaluate fatigue, depression and anxiety. Cases had lower average global DNA methylation than controls (81.2% vs 82.7%; p = 0.002). Four hundred and sixty-one differentially methylated regions, containing 3,246 probes mapping to 337 genes were identified. After adjustment for age and smoking, 731 probes in 236 genes were associated with psychopathology (fatigue, depression and/or anxiety). Twenty-four gene ontology terms were associated with psychopathology; terms related to retinoic acid receptor signalling were the most common (adjusted p = 0.0007). One gene in particular, COL11A2, was associated with fatigue following a false discovery rate correction. Our findings indicate that hypomethylation of FKBP5 and retinoic acid receptor related genes serve a potential mechanistic explanation for long-lasting GC-induced psychopathology.

Highlights

Hyperactivity of the hypothalamus-pituitary-adrenal (HPA)-axis, with subsequent increase in cortisol exposure at the tissue level[1,2], is implicated in neuropsychiatric disorders such as depression, post-traumatic stress disorder and anxiety[2,3,4,5,6,7,8,9]
Initial quality control (QC) analyses of the methylation raw data identified one case sample as a technical outlier due to low levels of detected CpG:s, this sample was removed from further analysis
We provide evidence for a distinguishable pattern of genome-wide DNA methylation in patients previously treated for Cushing’s syndrome (CS) and propose a mechanism for the long-term

Summary

Introduction

Hyperactivity of the hypothalamus-pituitary-adrenal (HPA)-axis, with subsequent increase in cortisol exposure at the tissue level[1,2], is implicated in neuropsychiatric disorders such as depression, post-traumatic stress disorder and anxiety[2,3,4,5,6,7,8,9]. In this part of the study the association between DNA methylation and fatigue, depression and anxiety in 48 women with CS in remission and 16 controls was analysed. We first performed DNA methylation analysis in ChAMP, to assess differences between patients with CS in long-term remission and matched controls (Table 2).

Results

Conclusion