title: Reduced DNA methylation and psychopathology following endogenous hypercortisolism - a genome-wide study.
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.
authors.affiliation: Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg and Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Camilla A M
authors.initials: CA
authors.lastname: Glad
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Andersson-Assarsson
authors.affiliation: Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Berglund
authors.affiliation: Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg and Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Ragnhildur
authors.initials: R
authors.lastname: Bergthorsdottir
authors.affiliation: Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg and Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Oskar
authors.initials: O
authors.lastname: Ragnarsson
authors.affiliation: Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg and Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Gudmundur
authors.initials: G
authors.lastname: Johannsson
mesh_terms: D000328:Adult; D000368:Aged; D001007:Anxiety / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D024161:Collagen Type XI / Q000235:genetics / Q000378:metabolism; D003430:Cross-Sectional Studies; D003480:Cushing Syndrome / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019175:DNA Methylation / Q000187:drug effects; D003863:Depression / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005221:Fatigue / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D015870:Gene Expression; D055106:Genome-Wide Association Study; D005938:Glucocorticoids / Q000009:adverse effects*; D006801:Humans; D006854:Hydrocortisone / Q000009:adverse effects*; D008875:Middle Aged; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D012074:Remission Induction; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
chemical_list: D015415:Biomarkers; D024161:Collagen Type XI; D005938:Glucocorticoids; D006854:Hydrocortisone; D018168:Receptors, Retinoic Acid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C499319:COL11A2 protein, human