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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., (© 2023. The Author(s).)

The experience of adversity in childhood has been associated with poor health outcomes in adulthood. In search of the biological mechanisms underlying these effects, research so far focused on alterations of DNA methylation or shifts in transcriptomic profiles. The level of protein, however, has been largely neglected. We utilized mass spectrometry to investigate the proteome of CD14 + monocytes in healthy adults reporting childhood adversity and a control group before and after psychosocial stress exposure. Particular proteins involved in (i) immune processes, such as neutrophil-related proteins, (ii) protein metabolism, or (iii) proteins related to mitochondrial biology, such as those involved in energy production processes, were upregulated in participants reporting exposure to adversity in childhood. This functional triad was further corroborated by protein interaction- and co-expression analyses, was independent of stress exposure, i.e. observed at both pre- and post-stress time points, and became evident especially in females. In line with the mitochondrial allostatic load model, our findings provide evidence for the long-term effects of childhood adversity on mitochondrial biology., (© 2023. The Author(s).)