Oxytocin receptor DNA methylation in postpartum depression

Abstract

The oxytocin receptor (OXTR) is a key regulator of stress and anxiety and may be regulated by both psychosocial risk factors and gonadal hormones, making it an attractive candidate for study in postpartum depression (PPD). The objective of this study was to investigate both serum hormone and PPD specific DNA methylation variation in the OXTR. Illumina HM450 microarray data generated in a prospective PPD cohort identified significant associations (P=0.014) with PPD in an intronic region in the OXTR located 4bp proximal to an estrogen receptor (ER) binding region. Pyrosequencing confirmed moderate evidence for an interaction of CpGs in the region with childhood abuse status to mediate PPD. These CpGs located on chr3 at positions 8810078 and 8810069 exhibited significant associations with postpartum depression scores from an independent cohort of 240 women with no prior psychiatric history. Hormone analysis suggested a PPD specific negative correlation of DNA methylation in the region with serum estradiol levels. Estradiol levels and OXTR DNA methylation exhibited a significant interaction to associate with the ratio of allopregnanolone to progesterone. Cumulatively, the data corroborate our previous hypotheses of a PPD specific increased sensitivity of epigenetic reprogramming at estrogen target genes and suggests that OXTR epigenetic variation may be an important mediator of mood relevant neuroactive steroid production.

Oxytocin pathways in the intergenerational transmission of maternal early life stress

“…Hypermethylation of this specific CpG has been shown to be associated with reduced OTR expression in the cortex of deceased autism patients (Gregory et al, 2009), suggesting that hypermethylation measured in peripheral tissue of this specific CpG may partly reflect OTR expression regulation in brain tissue (Bell et al, 2015). In contrast, another study found lower OXTR DNA methylation in an intronic region (cg 12695586) in women with high depressive symptoms both pre- and postpartum compared to women with PPD symptoms only (Kimmel et al, 2016). However, this study has important methodological weaknesses including very small sample sizes, and therefore replication of these findings is warranted to further clarify the role of OXTR DNA methylation in the etiology of PPD.…”

“…In addition to sequence variations in OT pathway genes, epigenetic modifications of the OXTR gene have recently attracted considerable attention in clinical, behavioral, and cognitive neurosciences (Kumsta et al, 2013) and have been associated with different phenotypes including maternal PPD (Bell et al, 2015; Kimmel et al, 2016), amygdala reactivity (Puglia et al, 2015), autism (Gregory et al, 2009), and social anxiety disorder (Ziegler et al, 2015) amongst others. Briefly, epigenetics encompasses a set of biochemical modifications of genome function (e.g., histone modifications, DNA methylation, or the effects of small non-coding RNAs, e.g., micro RNAs) that interfere with transcriptional or translational events and can therefore regulate gene expression.…”

“…Methylation-induced downregulation of the OTR was also confirmed in post mortem cortical brain tissue of male patients with autism spectrum disorders (Gregory et al, 2009). Two recent studies revealed a role for OXTR DNA methylation in peripheral blood cells to predict risk for PPD (Bell et al, 2015; Kimmel et al, 2016). GG homozygous (rs53576) women, who were not depressed during pregnancy had an almost 3-fold risk ( adjusted OR: 2.63 ) to develop PPD for every 10% increase of DNA methylation at a CpG dinucleotide located on intron 1, 934 basepairs upstream of the translation start site (CpG −934) compared to A allele carriers.…”

“…Taken together, it would be premature to draw general conclusions from the reported findings. Nevertheless, based on the exciting initial empirical evidence (Bell et al, 2015; Kimmel et al, 2016; Puglia et al, 2015), epigenetic modifications of the OXTR gene clearly deserve further attention when considering the role of OT-related intergenerational transmission pathways in the future.…”

Honing in On Hormone-Sensitive Neural Targets for Therapeutic Intervention: Mission Impossible?

“…In addition to serotonin, times of endocrine flux may also contribute to vulnerability by causing dysregulation in oxytocin (OT) signaling. Methylation of the OT receptor (OTR) gene is associated with diagnoses of anxiety and/ or depression in older women [3] and postpartum women [4]. The relationship between OT and affect may be enhanced during these periods because estradiol regulates both OT and OTR through activation of ER-β and -α, respectively [5].…”