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

• Published in: Scientific reports Vol. 7; no. 1; p. 44445
• Main Authors: Glad, Camilla A. M., Andersson-Assarsson, Johanna C., Berglund, Peter, Bergthorsdottir, Ragnhildur, Ragnarsson, Oskar, Johannsson, Gudmundur
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.03.2017; Nature Publishing Group
• Subjects: 45/22; 631/208/177; 631/337/176/1988; Adrenocorticotropic hormone; Anxiety; cognitive impairments; Cortisol; Cushing syndrome; cushings-syndrome; Deoxyribonucleic acid; DNA; DNA methylation; DNA probes; Endocrinology and Diabetes; Endokrinologi och diabetes; Fatigue; Gene mapping; Genes; Genomes; glucocorticoid-receptor; homeostatic synaptic plasticity; hpa-axis; Humanities and Social Sciences; major depressive disorder; Mental depression; multidisciplinary; Nervous system diseases; Pituitary; pituitary-adrenal axis; posttraumatic-stress-disorder; Probes; Psychopathology; receptor gene nr3c1; Remission; Science; Science & Technology - Other Topics; Smoking; trans-retinoic acid
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep44445

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.