Elsevier

Psychoneuroendocrinology

Volume 80, June 2017, Pages 67-73
Psychoneuroendocrinology

Methylation of HPA axis related genes in men with hypersexual disorder

https://doi.org/10.1016/j.psyneuen.2017.03.007Get rights and content

Highlights

  • Patients with hypersexual disorder had reduced levels of methylation in a locus of the CRH gene.

  • Patients with hypersexual disorder had higher (TNF)-α levels compared to healthy volunteers.

  • The methylation levels at the identified CRH site, cg23409074, were significantly correlated between blood and four different brain regions.

Abstract

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 850 K 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 2000 bp 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 48 bp 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.

Introduction

Hypersexual Disorder (HD) defined as non-paraphilic sexual desire disorder with components of impulsivity, compulsivity and behavioral addiction, was proposed as a diagnosis for the DSM 5 (Kafka, 2010). Even though limited, recent research demonstrated some overlapping features between HD and substance use disorders, including common neurotransmitter systems and dysregulated hypothalamic-pituitary-adrenal (HPA) axis function (Kraus et al., 2016, Chatzittofis et al., 2016). While the neurobiological underpinnings of hypersexual disorder largely remain to be elucidated, it has been proposed that HD may share characteristics with addictive behaviors with a reward deficiency component, in turn partly affected by both genetic and epigenetic factors (Blum et al., 2015).

Increasing evidence suggests that DNA methylation is implicated in the pathophysiology of most psychiatric disorders (Menke and Binder, 2014, Mill et al., 2008) and alterations in epigenetic patterns have an effect on brain functions (Ma et al., 2009). Variations in DNA methylation (the addition of a methyl group to the 5′-position of the cytosine pyrimidine ring) modify gene expression by inhibiting transcription or by recruiting specific proteins that alter the chromatin state. Epigenetic modifications, including DNA methylation and histone acetylation (involved in chromatin remodeling), are involved not only in brain functioning but also in sexual behavior. In animal models, epigenetic modifications have been shown to affect sexual behavior, influencing sociosexual behavior, partner preference and post-copulatory sexual selection (Matsuda, 2014, Zeh and Zeh, 2008, Wang et al., 2013). Direct evidence of epigenetic mechanisms in human sexual behavior is sparse and research has mainly focused on the role of epigenetics in sexual orientation (Ngun and Vilain, 2014). To our knowledge, no studies thus far have investigated epigenetic changes in hypersexual disorder.

Substantial translational evidence implicates impairments in glucocorticoid signaling in stress related psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Early life adversity increases risk for developing psychopathology (Teicher and Samson, 2013) through epigenetic modification of stress reactivity genes (Turecki and Meaney, 2016). We have previously reported that hypersexual disorder was associated to hyperactive HPA axis in male patients, irrespective of early life adversity (Chatzittofis et al., 2016) and men with HD had higher TNFα levels compared to healthy male volunteers (Jokinen et al., 2016).

In this study, we aimed to identify HPA-axis coupled CpG-sites, in which modifications of the epigenetic profile are associated with hypersexual disorder. Further, associations of methylation to gene expression were tested in an independent sample of healthy controls.

Section snippets

Ethics

The study protocols were approved by the Regional Ethical Review Board in Stockholm (Dnrs: 2013/1335-31/2) and the participants gave their written informed consent to the study.

Patients

The study population has been described previously in detail (Chatzittofis et al., 2016). Sixty-seven male patients with hypersexual disorder seeking psychotherapeutic treatment were recruited to the study at the Center for Andrology and Sexual Medicine (CASM) at the Karolinska University Hospital, a multidisciplinary

Behavior of the clinical outcome variables

In this study, comprising 54 patients diagnosed with hypersexual disorder and 33 healthy volunteers, we initially aimed to identify HPA-axis coupled CpG-sites, in which modifications of the epigenetic profile are associated with hypersexual disorder. The study group included only male subjects. Patients with HD scored significantly higher on the CTQ (p < 0.001) and had higher levels of plasma DST ACTH (p < 0.01) and TNF-alpha (p < 0.0001), and lower levels of plasma IL-6 (p < 0.01). In addition, HD

Discussion

In this study, we found that male patients with hypersexual disorder had reduced levels of methylation in a methylation locus (cg23409074) site located 48 bp upstream of the transcription start site of the CRH gene. Furthermore, this methylation locus was significantly positively correlated with CRH gene expression in an independent cohort of healthy male subjects. To our knowledge, this is the first report on epigenetic changes related to hypersexual disorder. We used genome-wide methylation

Role of funding source

Funding for this study was provided by the Swedish Research Council and the Swedish Brain Research Foundation (Helgi Schiöth) and through a regional agreement between Umeå University and Västerbotten County Council (ALF) and by grants provided by the Stockholm County Council (ALF) (Jussi Jokinen).

Acknowledgements

Methylation profiling was performed by the SNP&SEQ Technology Platform in Uppsala (www.genotyping.se). The facility is part of the National Genomics Infrastructure (NGI) Sweden and Science for Life Laboratory. The SNP&SEQ Platform is also supported by the Swedish Research Council and the Knut and Alice Wallenberg Foundation. DNA extraction was performed by Latvian BMC, funded by the Latvian Council of Science European Social Fund and European Regional Development Fund.

References (49)

  • L. Regev et al.

    Corticotropin releasing factor in neuroplasticity

    Front. Neuroendocrinol.

    (2014)
  • R.C. Reid et al.

    Report of findings in a DSM-5 field trial for hypersexual disorder

    J. Sex. Med.

    (2012)
  • P. Svanborg et al.

    A comparison between the beck depression inventory (BDI) and the self-rating version of the montgomery asberg depression rating scale (MADRS)

    J. Affect. Disord.

    (2001)
  • G. Turecki et al.

    Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review

    Biol. Psychiatry

    (2016)
  • E.P. Zorrilla et al.

    Corticotropin releasing factor: a key role in the neurobiology of addiction

    Front. Neuroendocrinol.

    (2014)
  • L. Arborelius et al.

    The role of corticotropin-releasing factor in depression and anxiety disorders

    J. Endocrinol.

    (1999)
  • M.J. Aryee et al.

    Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays

    Bioinformatics

    (2014)
  • Y. Benjamini et al.

    Controlling the False Discovery Rate: a practical and powerful approach to multiple testing

    J. R. Stat. Soc. Ser. B

    (1995)
  • D.P. Bernstein et al.

    Childhood Trauma Questionnaire: A Retrospective Self-Report Manual

    (1998)
  • K. Blum et al.

    Hypersexuality addiction and withdrawal: phenomenology, neurogenetics and epigenetics

    Cureus

    (2015)
  • J. Chen et al.

    Maternal deprivation in rats is associated with corticotrophin-releasing hormone (CRH) promoter hypomethylation and enhances CRH transcriptional responses to stress in adulthood

    J. Neuroendocrinol.

    (2012)
  • R. Dantzer et al.

    From inflammation to sickness and depression: when the immune system subjugates the brain

    Nat. Rev. Neurosci.

    (2008)
  • P. Du et al.

    Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis

    BMC Bioinf.

    (2010)
  • F.R. Hampel et al.

    Robust Statistics: the Approach Based on Influence of Functions

    (1986)
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