Methylation of HPA axis related genes in men with hypersexual disorder.
Hypersexual Disorder (HD) defined as non-paraphilic sexual desire disorder with components of compulsivity, impulsivity and behavioral addiction, and proposed as a diagnosis in the DSM 5, shares some overlapping features with substance use disorder including common neurotransmitter systems and dysregulated hypothalamic-pituitary-adrenal (HPA) axis function. In this study, comprising 67 HD male patients and 39 male healthy volunteers, we aimed to identify HPA-axis coupled CpG-sites, in which modifications of the epigenetic profile are associated with hypersexuality. The genome-wide methylation pattern was measured in whole blood using the Illumina Infinium Methylation EPIC BeadChip, measuring the methylation state of over 850K CpG sites. Prior to analysis, the global DNA methylation pattern was pre-processed according to standard protocols and adjusted for white blood cell type heterogeneity. We included CpG sites located within 2000bp of the transcriptional start site of the following HPA-axis coupled genes: Corticotropin releasing hormone (CRH), corticotropin releasing hormone binding protein (CRHBP), corticotropin releasing hormone receptor 1 (CRHR1), corticotropin releasing hormone receptor 2 (CRHR2), FKBP5 and the glucocorticoid receptor (NR3C1). We performed multiple linear regression models of methylation M-values to a categorical variable of hypersexuality, adjusting for depression, dexamethasone non-suppression status, Childhood Trauma Questionnaire total score and plasma levels of TNF-alpha and IL-6. Of 76 tested individual CpG sites, four were nominally significant (p<0.05), associated with the genes CRH, CRHR2 and NR3C1. Cg23409074-located 48bp upstream of the transcription start site of the CRH gene - was significantly hypomethylated in hypersexual patients after corrections for multiple testing using the FDR-method. Methylation levels of cg23409074 were positively correlated with gene expression of the CRH gene in an independent cohort of 11 healthy male subjects. The methylation levels at the identified CRH site, cg23409074, were significantly correlated between blood and four different brain regions. CRH is an important integrator of neuroendocrine stress responses in the brain, with a key role in the addiction processes. Our results show epigenetic changes in the CRH gene related to hypersexual disorder in men.
Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Sciences/Psychiatry, Umeå University, Umeå, Sweden. Electronic address: jussi.jokinen@ki.se.
Jussi
J
Jokinen
Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Adrian E
AE
Boström
Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Stockholm, Sweden; Medical School, University of Cyprus, Nicosia, Cyprus.
Andreas
A
Chatzittofis
Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Diana M
DM
Ciuculete
Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Katarina Görts
KG
Öberg
Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
John N
JN
Flanagan
Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Stefan
S
Arver
Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Helgi B
HB
Schiöth
D000328:Adult; D003346:Corticotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008745:Methylation; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D020018:Sexual Dysfunctions, Psychological / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D013315:Stress, Psychological / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5
D003346:Corticotropin-Releasing Hormone; D015850:Interleukin-6; D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5; C497713:NR3C1 protein, human
Childhood trauma; Cortisol; Dexamethasone test; Epigenetics; HPA-axis; Hypersexual disorder; Methylation; Neuroinflammation; TNF-alpha