The DNA methylation landscape of the human oxytocin receptor gene (OXTR): data-driven clusters and their relation to gene expression and childhood adversity.
[en] The oxytocin receptor gene (OXTR) is of interest when investigating the effects of early adversity on DNA methylation. However, there is heterogeneity regarding the selection of the most promising CpG sites to target for analyses. The goal of this study was to determine functionally relevant clusters of CpG sites within the OXTR CpG island in 113 mother-infant dyads, with 58 of the mothers reporting childhood maltreatment (CM). OXTR DNA methylation was analyzed in peripheral/umbilical blood mononuclear cells. Different complexity reduction approaches were used to reduce the 188 CpG sites into clusters of co-methylated sites. Furthermore, associations between OXTR DNA methylation (cluster- and site-specific level) and OXTR gene expression and CM were investigated in mothers. Results showed that, first, CpG sections differed strongly regarding their statistical utility for research of individual differences in DNA methylation. Second, cluster analyses and Partial Least Squares (PLS) suggested two clusters consisting of intron1/exon2 and the protein-coding region of exon3, respectively, as most strongly associated with outcome measures. Third, cross-validated PLS regression explained 7% of variance in CM, with low cross-validated variance explained for the prediction of gene expression. Fourth, substantial mother-child correspondence was observed in correlation patterns within the identified clusters, but only modest correspondence outside these clusters. This study makes an important contribution to the mapping of the DNA methylation landscape of the OXTR CpG island by highlighting clusters of CpG sites that show desirable statistical properties and predictive value. We provide a Companion Web Application to facilitate the choice of CpG sites.
Disciplines :
Neurosciences & behavior
Author, co-author :
Müller, Svenja
Sicorello, Maurizio
Moser, Dirk
Frach, Leonard
Limberg, Alicia
Gumpp, Anja M.
Ramo-Fernandez, Laura
Köhler-Dauner, Franziska
Fegert, Jörg M.
Waller, Christiane
KUMSTA, Robert ; University of Luxembourg > Faculty of Humanities, Education and Social Sciences (FHSE) > Department of Behavioural and Cognitive Sciences (DBCS)
Kolassa, Iris-Tatjana
External co-authors :
yes
Language :
English
Title :
The DNA methylation landscape of the human oxytocin receptor gene (OXTR): data-driven clusters and their relation to gene expression and childhood adversity.
Publication date :
2023
Journal title :
Translational Psychiatry
ISSN :
2158-3188
Publisher :
Springer Nature, New-York, United States - New York
Feldman R, Monakhov M, Pratt M, Ebstein RP. Oxytocin pathway genes: evolutionary ancient system impacting on human affiliation, sociality, and psychopathology. Biol Psychiatry. 2016;79:174–84. DOI: 10.1016/j.biopsych.2015.08.008
Hammock EAD. Developmental perspectives on oxytocin and vasopressin. Neuropsychopharmacology 2015;40:24–42. DOI: 10.1038/npp.2014.120
Heinrichs M, von Dawans B, Domes G. Oxytocin, vasopressin, and human social behavior. Front Neuroendocrinol. 2009;30:548–57. DOI: 10.1016/j.yfrne.2009.05.005
Baribeau DA, Anagnostou E. Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social neurocircuits. Front Neurosci. 2015;9:335. DOI: 10.3389/fnins.2015.00335
Grinevich V, Stoop R. Interplay between oxytocin and sensory systems in the orchestration of socio-emotional behaviors. Neuron 2018;99:887–904. DOI: 10.1016/j.neuron.2018.07.016
Kompier NF, Keysers C, Gazzola V, Lucassen PJ, Krugers HJ. Early life adversity and adult social behavior: focus on arginine vasopressin and oxytocin as potential mediators. Front Behav Neurosci. 2019;13:143. DOI: 10.3389/fnbeh.2019.00143
Perkeybile AM, Carter CS, Wroblewski KL, Puglia MH, Kenkel WM, Lillard TS, et al. Early nurture epigenetically tunes the oxytocin receptor. Psychoneuroendocrinology 2019;99:128–36. DOI: 10.1016/j.psyneuen.2018.08.037
Ellis BJ, Horn AJ, Carter CS, van IJzendoorn MH, Bakermans-Kranenburg MJ. Developmental programming of oxytocin through variation in early-life stress: Four meta-analyses and a theoretical reinterpretation. Clin Psychol Rev. 2021;86:101985. DOI: 10.1016/j.cpr.2021.101985
Kraaijenvanger EJ, He Y, Spencer H, Smith AK, Bos PA, Boks MPM. Epigenetic variability in the human oxytocin receptor (OXTR) gene: A possible pathway from early life experiences to psychopathologies. Neurosci Biobehav Rev. 2019;96:127–42. DOI: 10.1016/j.neubiorev.2018.11.016
Kumsta R, Hummel E, Chen FS, Heinrichs M. Epigenetic regulation of the oxytocin receptor gene: implications for behavioral neuroscience. Front Neurosci. 2013;7:83. DOI: 10.3389/fnins.2013.00083
Kusui C, Kimura T, Ogita K, Nakamura H, Matsumura Y, Koyama M, et al. DNA methylation of the human oxytocin receptor gene promoter regulates tissue-specific gene suppression. Biochem Biophys Res Commun. 2001;289:681–6. DOI: 10.1006/bbrc.2001.6024
Needham BL, Smith JA, Zhao W, Wang X, Mukherjee B, Kardia SLR, et al. Life course socioeconomic status and DNA methylation in genes related to stress reactivity and inflammation: The multi-ethnic study of atherosclerosis. Epigenetics 2015;10:958–69. DOI: 10.1080/15592294.2015.1085139
Unternaehrer E, Meyer AH, Burkhardt SCA, Dempster E, Staehli S, Theill N, et al. Childhood maternal care is associated with DNA methylation of the genes for brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OXTR) in peripheral blood cells in adult men and women. Stress 2015;18:451–61. DOI: 10.3109/10253890.2015.1038992
Fujisawa TX, Nishitani S, Takiguchi S, Shimada K, Smith AK, Tomoda A. Oxytocin receptor DNA methylation and alterations of brain volumes in maltreated children. Neuropsychopharmacology 2019;44:2045–53. DOI: 10.1038/s41386-019-0414-8
Gouin JP, Zhou QQ, Booij L, Boivin M, Côté SM, Hébert M, et al. Associations among oxytocin receptor gene (OXTR) DNA methylation in adulthood, exposure to early life adversity, and childhood trajectories of anxiousness. Sci Rep. 2017;7:7446. DOI: 10.1038/s41598-017-07950-x
Smearman EL, Almli LM, Conneely KN, Brody GH, Sales JM, Bradley B, et al. Oxytocin receptor genetic and epigenetic variations: association with child abuse and adult psychiatric symptoms. Child Dev. 2016;87:122–34. DOI: 10.1111/cdev.12493
Robakis TK, Zhang S, Rasgon NL, Li T, Wang T, Roth MC, et al. Epigenetic signatures of attachment insecurity and childhood adversity provide evidence for role transition in the pathogenesis of perinatal depression. Transl Psychiatry. 2020;10:48. DOI: 10.1038/s41398-020-0703-3
Krol KM, Moulder RG, Lillard TS, Grossmann T, Connelly JJ. Epigenetic dynamics in infancy and the impact of maternal engagement. Sci Adv. 2019;5:eaay0680. DOI: 10.1126/sciadv.aay0680
King L, Robins S, Chen G, Yerko V, Zhou Y, Nagy C, et al. Perinatal depression and DNA methylation of oxytocin-related genes: a study of mothers and their children. Horm Behav. 2017;96:84–94. DOI: 10.1016/j.yhbeh.2017.09.006
Ramo-Fernández L, Gumpp AM, Boeck C, Krause S, Bach AM, Waller C, et al. Associations between childhood maltreatment and DNA methylation of the oxytocin receptor gene in immune cells of mother–newborn dyads. Transl Psychiatry. 2021;11:449. DOI: 10.1038/s41398-021-01546-w
Inoue T, Kimura T, Azuma C, Inazawa J, Takemura M, Kikuchi T, et al. Structural organization of the human oxytocin receptor gene. J Biol Chem. 1994;269:32451–6. DOI: 10.1016/S0021-9258(18)31656-9
Moser DA, Müller S, Hummel EM, Limberg AS, Dieckmann L, Frach L, et al. Targeted bisulfite sequencing: A novel tool for the assessment of DNA methylation with high sensitivity and increased coverage. Psychoneuroendocrinology 2020;120:104784. DOI: 10.1016/j.psyneuen.2020.104784
Bader K, Hänny C, Schäfer V, Neuckel A, Kuhl C. Childhood trauma questionnaire – psychometrische eigenschaften einer deutschsprachigen version. Z Für Klin Psychol Psychother. 2009;38:223–30. DOI: 10.1026/1616-3443.38.4.223
Berstein DP, Fink L. Childhood trauma questionnaire: a retrospective self-report manual. San Antonio, TX: Psychological Corporation, 1998.
Leitão E, Beygo J, Zeschnigk M, Klein-Hitpass L, Bargull M, Rahmann S, et al. (2018). Locus-Specific DNA Methylation Analysis by Targeted Deep Bisulfite Sequencing. In: Jeltsch A, Rots M (eds). Epigenome Editing: Methods in Molecular Biology. Humana Press: New York, 2018;1767;351–66.
Rahmann S, Beygo J, Kanber D, Martin M, Horsthemke B, Buiting K. Amplikyzer: Automated methylation analysis of amplicons from bisulfite flowgram sequencing. PeerJ Prepr. 2013;1:e122v2.
Andersen CL, Jensen JL, Ørntoft TF. Normalization of real-time quantitative reverse transcription-PCR data: A model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res. 2004;64:5245–50. DOI: 10.1158/0008-5472.CAN-04-0496
Hahsler M, Piekenbrock M, Doran D. dbscan: Fast density-based clustering with R. J Stat Softw. 2019;91:1–30. DOI: 10.18637/jss.v091.i01
Kuhn M, Wing J, Weston S, Williams A, Keefer C, Engelhardt A, et al. (2021). caret: Classification and Regression Training. R package version v6.0-90. https://CRAN.R-project.org/package=caret.
Liland KH, Mevik B-H, Wehrens R, Hiemstra P (2021). pls: Partial Least Squares and Principal Component Regression. R package version v2.8-0. https://CRAN.R-project.org/package=pls.
Chén OY, Crainiceanu C, Ogburn EL, Caffo BS, Wager TD, Lindquist MA. High-dimensional multivariate mediation with application to neuroimaging data. Biostatistics 2018;19:121–36. DOI: 10.1093/biostatistics/kxx027
Geuter S, Reynolds Losin EA, Roy M, Atlas LY, Schmidt L, Krishnan A, et al. Multiple brain networks mediating stimulus–pain relationships in humans. Cereb Cortex. 2020;30:4204–19. DOI: 10.1093/cercor/bhaa048
Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47. DOI: 10.1093/nar/gkv007
Peters TJ, Buckley MJ, Statham AL, Pidsley R, Samaras K, V Lord R, et al. De novo identification of differentially methylated regions in the human genome. Epigenetics Chromatin. 2015;8:6. DOI: 10.1186/1756-8935-8-6
Chen Y, Pal B, Visvader JE, Smyth GK. Differential methylation analysis of reduced representation bisulfite sequencing experiments using edgeR. F1000Res. 2017;6:2055. DOI: 10.12688/f1000research.13196.1
Lecompte V, Robins S, King L, Solomonova E, Khan N, Moss E, et al. Examining the role of mother-child interactions and DNA methylation of the oxytocin receptor gene in understanding child controlling attachment behaviors. Attach Hum Dev. 2021;23:37–55. DOI: 10.1080/14616734.2019.1708422
Lancaster K, Morris JP, Connelly JJ. Neuroimaging epigenetics: challenges and recommendations for best practices. Neuroscience 2018;370:88–100. DOI: 10.1016/j.neuroscience.2017.08.004
Jones MJ, Moore SR, Kobor MS. Principles and challenges of applying epigenetic epidemiology to psychology. Annu Rev Pychol. 2018;69:459–85. DOI: 10.1146/annurev-psych-122414-033653
Almeida D, Fiori LM, Chen GG, Aouabed Z, Lutz P-E, Zhang T-Y, et al. Oxytocin receptor expression and epigenetic regulation in the anterior cingulate cortex of individuals with a history of severe childhood abuse. Psychoneuroendocrinology 2022;136:105600. DOI: 10.1016/j.psyneuen.2021.105600