Hypermethylation-associated downregulation of microRNA-4456 in hypersexual disorder with putative influence on oxytocin signalling: A DNA methylation analysis of miRNA genes
Open accessAbstract
Hypersexual disorder (HD) was proposed as a diagnosis in the DSM-5 and the classification ‘Compulsive Sexual Behavior Disorder’ is now presented as an impulse-control disorder in ICD-11. HD incorporates several pathophysiological mechanisms; including impulsivity, compulsivity, sexual desire dysregulation and sexual addiction. No previous study investigated HD in a methylation analysis limited to microRNA (miRNA) associated CpG-sites. The genome wide methylation pattern was measured in whole blood from 60 subjects with HD and 33 healthy volunteers using the Illumina EPIC BeadChip. 8,852 miRNA associated CpG-sites were investigated in multiple linear regression analyses of methylation M-values to a binary independent variable of disease state (HD or healthy volunteer), adjusting for optimally determined covariates. Expression levels of candidate miRNAs were investigated in the same individuals for differential expression analysis. Candidate methylation loci were further studied for an association with alcohol dependence in an independent cohort of 107 subjects. Two CpG-sites were borderline significant in HD – cg18222192 (MIR708)(p < 10E-05,pFDR = 5.81E-02) and cg01299774 (MIR4456)(p < 10E-06, pFDR = 5.81E-02). MIR4456 was significantly lower expressed in HD in both univariate (p < 0.0001) and multivariate (p < 0.05) analyses. Cg01299774 methylation levels were inversely correlated with expression levels of MIR4456 (p < 0.01) and were also differentially methylated in alcohol dependence (p = 0.026). Gene target prediction and pathway analysis revealed that MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signalling pathway. In summary, our study implicates a potential contribution of MIR4456 in the pathophysiology of HD by putatively influencing oxytocin signalling.
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MIR4456 had lower expression in males reporting versus those not reporting compulsive sexual behaviour, and it was posited that this gene may play an important role in the oxytocin signaling pathway related to the expression of the behaviour.
“They found that MIR4456 (an mRNA gene) had lower expression in males reporting vs. those not reporting the behaviour, and posited that this gene may play an important role in the oxytocin signaling pathway related to the expression of the behaviour 278 .”
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Self-citation
- Authors
- Boström, A. E., Chatzittofis, A., Ciuculete, D.-M., Flanagan, J. N., Krattinger, R., Bandstein, M., Mwinyi, J., Kullak-Ublick, G. A., Öberg, K. G., Arver, S., Schiöth, H. B., & Jokinen, J.
- Affiliations
- Uppsala University (SE)
- Umeå University (SE)
- Karolinska Institutet (SE)
- University of Zurich (CH)
- Corresponding author
- Boström, Adrian E.
- ORCID
- Venue
- Epigenetics
- Publisher
- Informa UK Limited
- Published
- 2019-09-22
- Volume
- 15
- Issue
- 1-2
- Pages
- 145-160
- ISSN
- 1559-2294 (ISSN-L)
- 1559-2308
- PMC
- PMC6961682
- OpenAlex
- W2973725019
- Cited by
- 25
- References
- 70
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 1 · 2022: 9 · 2021: 4 · 2020: 5
- FWCI
- 5.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Epigenetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Latvijas Zinātnes Padome
- Uppsala Universitet
- Science for Life Laboratory
- European Regional Development Fund
- European Social Fund
- Topics
- Social Sciences › Psychology › Clinical Psychology › Sexuality, Behavior, and Technology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- hypersexual disorder, compulsive sexual behavior disorder, DNA methylation, alcoholism, CpG sites, miRNA genes, sexual addiction, compulsivity
- MeSH terms
- Adult, Aged, Mental Disorders, Female, Humans, Male, Middle Aged, Oxytocin, Sexual Behavior, Signal Transduction, Down-Regulation, DNA Methylation, MicroRNAs
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