Replication of Epigenetic Postpartum Depression Biomarkers and Variation with Hormone Levels

Osborne, Lauren M.; Clive, Makena; Kimmel, Mary; Gispen, Fiona; Guintivano, Jerry; Brown, Tori; Cox, Olivia; Judy, Jennifer; Meilman, Samantha; Braier, Aviva; Beckmann, Matthias W.; Kornhuber, Johannes; Fasching, Peter A.; Goes, Fernando S.; Payne, Jennifer L.; Binder, Elisabeth B.; Kaminsky, Zachary

doi:10.1038/npp.2015.333

Cited by 77 publications

(55 citation statements)

References 57 publications

(73 reference statements)

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“…Another behavioral state with a major impact on maternal care is depression, and post‐partum depressive behavior is associated with reduced maternal care in both humans (Field ) and mice (Maguire & Mody ). Interestingly, and apparently consistent with our own notion in mice, it was recently reported that the hyper‐methylation status of the HP1BP3 gene promoter in blood DNA from pregnant women was an excellent antenatal predictor of PPD (Guintivano et al ; Osborne et al ). One potential cause for post‐partum anxiety is altered cholinergic status (Grisaru et al ); however, we excluded that cause by demonstrating that Hp1bp3 −/− mice sustained unchanged circulation cholinesterase activities as compared to normal controls.…”

Section: Discussionsupporting

confidence: 89%

HP1BP3 expression determines maternal behavior and offspring survival

Garfinkel

Arad

Neuner

et al. 2016

Genes Brain and Behavior

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Maternal care is an indispensable behavioral component necessary for survival and reproductive success in mammals, and postpartum maternal behavior is mediated by an incompletely understood complex interplay of signals including effects of epigenetic regulation. We approached this issue using our recently established mice with targeted deletion of heterochromatin protein 1 binding protein 3 (HP1BP3), which we found to be a novel epigenetic repressor with critical roles in postnatal growth. Here, we report a dramatic reduction in the survival of pups born to Hp1bp3(-/-) deficient mouse dams, which could be rescued by co-fostering with wild-type dams. Hp1bp3(-/-) females failed to retrieve both their own pups and foster pups in a pup retrieval test, and showed reduced anxiety-like behavior in the open-field and elevated-plus-maze tests. In contrast, Hp1bp3(-/-) females showed no deficits in behaviors often associated with impaired maternal care, including social behavior, depression, motor coordination and olfactory capability; and maintained unchanged anxiety-associated hallmarks such as cholinergic status and brain miRNA profiles. Collectively, our results suggest a novel role for HP1BP3 in regulating maternal and anxiety-related behavior in mice and call for exploring ways to manipulate this epigenetic process.

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Section: Discussionsupporting

confidence: 89%

HP1BP3 expression determines maternal behavior and offspring survival

Garfinkel

Arad

Neuner

et al. 2016

Genes Brain and Behavior

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“…With respect to perinatal depression, two regions of alternative DNA methylation in association with postpartum depression have been previously identified in leukocytes, resulting from a screen that was designed to identify DNA methylation effects of estrogen activity 25,26 . Later work from this dataset using a candidate-gene approach also identified alterations in methylation density within the oxytocin receptor gene in association with postpartum depression 27 .…”

Section: Molecular Pathways From Early Life Adversity To Adult Perinamentioning

confidence: 99%

Epigenetic signatures of attachment insecurity and childhood adversity provide evidence for role transition in the pathogenesis of perinatal depression

et al. 2020

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Early life adversity and insecure attachment style are known risk factors for perinatal depression. The biological pathways linking these experiences, however, have not yet been elucidated. We hypothesized that overlap in patterns of DNA methylation in association with each of these phenomena could identify genes and pathways of importance. Specifically, we wished to distinguish between allostatic-load and role-transition hypotheses of perinatal depression. We conducted a large-scale analysis of methylation patterns across 5 × 10 6 individual CG dinucleotides in 54 women participating in a longitudinal prospective study of perinatal depression, using clustering-based criteria for significance to control for multiple comparisons. We identified 1580 regions in which methylation density was associated with childhood adversity, 3 in which methylation density was associated with insecure attachment style, and 6 in which methylation density was associated with perinatal depression. Shorter telomeres were observed in association with childhood trauma but not with perinatal depression or attachment insecurity. A detailed analysis of methylation density in the oxytocin receptor gene revealed similar patterns of DNA methylation in association with perinatal depression and with insecure attachment style, while childhood trauma was associated with a distinct methylation pattern in this gene. Clinically, attachment style was strongly associated with depression only in pregnancy and the early postpartum, whereas the association of childhood adversity with depression was time-invariant. We concluded that the broad DNA methylation signature and reduced telomere length associated with childhood adversity could indicate increased allostatic load across multiple body systems, whereas perinatal depression and attachment insecurity may be narrower phenotypes with more limited DNA methylation signatures outside the CNS, and no apparent association with telomere length or, by extension, allostatic load. In contrast, the finding of matching DNA methylation patterns within the oxytocin receptor gene for perinatal depression and attachment insecurity is consistent with the theory that the perinatal period is a time of activation of existing attachment schemas for the purpose of structuring the mother-child relationship, and that such activation may occur in part through specific patterns of methylation of the oxytocin receptor gene.

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“…A challenge for the identification of peripheral tissue-based epigenetic biomarkers in the context of psychiatry is the generalizability of the identified peripheral epigenetic variation in the brain. We have hypothesized previously that circulating steroid hormones such as cortisol may mark peripheral tissue DNA on the epigenetic level while affecting behavior through central nervous system (CNS) specific actions [15–17]. In support of this hypothesis, the initial objective of this study was to evaluate if cortisol-associated DNA methylation levels in peripheral tissues (blood and saliva) are enriched among suicide-associated DNA methylation levels in the brain.…”

Section: Introductionmentioning

confidence: 99%

Discovery and replication of a peripheral tissue DNA methylation biosignature to augment a suicide prediction model

et al. 2016

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BackgroundSuicide is the second leading cause of death among adolescents in the USA, and rates are rising. Methods to identify individuals at risk are essential for implementing prevention strategies, and the development of a biomarker can potentially improve prediction of suicidal behaviors. Prediction of our previously reported SKA2 biomarker for suicide and PTSD is substantially improved by questionnaires assessing perceived stress or anxiety and is therefore reliant on psychological assessment. However, such stress-related states may also leave a biosignature that could equally improve suicide prediction. In genome-wide DNA methylation data, we observed significant overlap between waking cortisol-associated and suicide-associated DNA methylation in blood and the brain, respectively.ResultsUsing a custom bioinformatic brain to blood discovery algorithm, we derived a DNA methylation biosignature that interacts with SKA2 methylation to improve the prediction of suicidal ideation in our existing suicide prediction model across both blood and saliva data sets. This biosignature was independently validated in the Grady Trauma Project cohort and interacted with HPA axis metrics in the same cohort. The biosignature showed a relationship with immune status by its correlation with myeloid-derived cell proportions in all data sets and with IL-6 measures in a prospective postpartum depression cohort. Three probes showed significant correlations with the biosignature: cg08469255 (DDR1), cg22029879 (ARHGEF10), and cg24437859 (SHP1), of which SHP1 methylation correlated with immune measures.ConclusionsWe conclude that this biosignature interacts with SKA2 methylation to improve suicide prediction and may represent a biological state of immune and HPA axis modulation that mediates suicidal behavior.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0279-1) contains supplementary material, which is available to authorized users.

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Replication of Epigenetic Postpartum Depression Biomarkers and Variation with Hormone Levels

Cited by 77 publications

References 57 publications

HP1BP3 expression determines maternal behavior and offspring survival

HP1BP3 expression determines maternal behavior and offspring survival

Epigenetic signatures of attachment insecurity and childhood adversity provide evidence for role transition in the pathogenesis of perinatal depression

Discovery and replication of a peripheral tissue DNA methylation biosignature to augment a suicide prediction model

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