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HPA axis dysregulation is associated with differential methylation of CpG-sites in related genes
Univ Cyprus, Med Sch, CY-1678 Nicosia, Cyprus.;Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden..
Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth, Neuropaediat Unit, Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.ORCID iD: 0000-0001-6377-0270
Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
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2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 20134Article in journal (Refereed) Published
Abstract [en]

DNA methylation shifts in Hypothalamic-pituitary-adrenal (HPA) axis related genes is reported in psychiatric disorders including hypersexual disorder. This study, comprising 20 dexamethasone suppression test (DST) non-suppressors and 73 controls, examined the association between the HPA axis dysregulation, shifts in DNA methylation of HPA axis related genes and importantly, gene expression. Individuals with cortisol level >= 138 nmol/l, after the low dose (0.5 mg) dexamethasone suppression test (DST) were classified as non-suppressors. Genome-wide methylation pattern, measured in whole blood using the EPIC BeadChip, investigated CpG sites located within 2000 bp of the transcriptional start site of key HPA axis genes, i.e.: CRH, CRHBP, CRHR-1, CRHR-2, FKBP5 and NR3C1. Regression models including DNA methylation M-values and the binary outcome (DST non-suppression status) were performed. Gene transcripts with an abundance of differentially methylated CpG sites were identified with binomial tests. Pearson correlations and robust linear regressions were performed between CpG methylation and gene expression in two independent cohorts. Six of 76 CpG sites were significantly hypermethylated in DST non-suppressors (nominal P < 0.05), associated with genes CRH, CRHR1, CRHR2, FKBP5 and NR3C1. NR3C1 transcript AJ877169 showed statistically significant abundance of probes differentially methylated by DST non-suppression status and correlated with DST cortisol levels. Further, methylation levels of cg07733851 and cg27122725 were positively correlated with gene expression levels of the NR3C1 gene. Methylation levels of cg08636224 (FKBP5) correlated with baseline cortisol and gene expression. Our findings revealed that DNA methylation shifts are involved in the altered mechanism of the HPA axis suggesting that new epigenetic targets should be considered behind psychiatric disorders.

Place, publisher, year, edition, pages
Springer Nature Springer Nature, 2021. Vol. 11, no 1, article id 20134
National Category
Psychiatry Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-458317DOI: 10.1038/s41598-021-99714-xISI: 000706395800055PubMedID: 34635736OAI: oai:DiVA.org:uu-458317DiVA, id: diva2:1609870
Funder
Swedish Research Council, 202001183Available from: 2021-11-09 Created: 2021-11-09 Last updated: 2024-01-15Bibliographically approved

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