Intrinsically dysregulated cellular stress signaling genes and gene networks in postpartum depression

Rudzinskas, Sarah; Goff, Allison; Mazzu, Maria; Schiller, Crystal Edler; Meltzer‐Brody, Samantha; Rubinow, David R.; Schmidt, Peter J.; Goldman, David

doi:10.1038/s41380-023-01985-5

Cited by 7 publications

(10 citation statements)

References 80 publications

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“…We previously hypothesized that women with PPD have an innate cellular sensitivity to changes in ovarian steroids that underlies their affective symptoms [ 18 ]. Recent findings from our patient-derived, lymphoblastoid cell lines (LCLs) support this hypothesis, demonstrating intrinsically different transcriptomes in PPD LCLs compared to controls, both in the absence of exogenous hormonal variation (baseline) and in response to the addition and removal of estradiol (E2) and P4 [ 19 ]. These in vitro data provide a possible biological basis for the clinical observation that the recapitulation of ovarian steroid changes occurring peripartum can trigger a recurrence of mood symptoms in women with past PPD but not matched postpartum controls [ 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 70%

“…Epstein-Barr Virus generation, passaging and maintenance for LCLs prior to the experimental ALLO treatments are as described in Rudzinskas et al, 2023 [ 19 ]. For the present study, N = 19 LCLs were utilized, comprising n = 10 derived from women without a history of PPD (i.e., Controls) and n = 9 from women with past PPD (i.e., PPD).…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, our in vitro findings [ 19 ] of intrinsic transcriptomic differences in PPD LCLs raise questions about ALLO’s genomic effects. Namely, what are the downstream cellular responses to ALLO, and do these responses differ for, or mitigate differences in, the PPD transcriptome?…”

Section: Introductionmentioning

confidence: 99%

“…To investigate these questions, here we subject our previously described [ 19 ] PPD LCL model to 60 h of ALLO-treatment and utilize transcriptomics to characterize and compare gene expression thereafter. Our goal was to identify ALLO-related transcriptomic changes (or lack thereof) in both PPD and control LCLs that could potentially be involved in ALLO’s antidepressant mechanisms for PPD.…”

Section: Introductionmentioning

confidence: 99%

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Divergent Transcriptomic Effects of Allopregnanolone in Postpartum Depression

Rudzinskas

Mazzu

Schiller

et al. 2023

Genes

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Brexanolone, a formulation of the neurosteroid allopregnanolone (ALLO), is approved for treating postpartum depression (PPD) and is being investigated for therapeutic efficacy across numerous neuropsychiatric disorders. Given ALLO’s beneficial effects on mood in women with PPD compared to healthy control women, we sought to characterize and compare the cellular response to ALLO in women with (n = 9) or without (n = 10, i.e., Controls) past PPD, utilizing our previously established patient-derived lymphoblastoid cell lines (LCLs). To mimic in vivo PPD ALLO-treatment, LCLs were exposed to ALLO or DMSO vehicle for 60 h and RNA-sequenced to detect differentially expressed genes (DEGs, pnominal < 0.05). Between ALLO-treated Control and PPD LCLs, 269 DEGs were identified, including Glutamate Decarboxylase 1 (GAD1), which was decreased 2-fold in PPD. Network analysis of PPD:ALLO DEGs revealed enriched terms related to synaptic activity and cholesterol biosynthesis. Within-diagnosis analyses (i.e., DMSO vs. ALLO) detected 265 ALLO-induced DEGs in Control LCLs compared to only 98 within PPD LCLs, with just 11 DEGs overlapping. Likewise, the gene ontologies underlying ALLO-induced DEGs in PPD and Control LCLs were divergent. These data suggest that ALLO may activate unique and opposing molecular pathways in women with PPD, which may be tied to its antidepressant mechanism.

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Section: Introductionmentioning

confidence: 70%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Divergent Transcriptomic Effects of Allopregnanolone in Postpartum Depression

Rudzinskas

Mazzu

Schiller

et al. 2023

Genes

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“…Since no significant difference in absolute oestrogen levels was found, the study concluded that the pertinent factor for PND was response to oestrogen. Later studies by the same group supported this conclusion [78, 79], and a recent study reported dysregulated cellular stress signalling genes following exposure to oestrogen within cell lines taken from women with a history of PND compared to controls [80]. The 11p14.1 locus, containing FSHB and ARL14EP and associated with the release of oestrogen, ranked highest for the latent reproductive factor and was nominally significant for both female depression and MD, and the 6q25.2 locus, containing ESR1 , was nominally associated with three depression groups (MD, female depression, and PND).…”

Section: Discussionmentioning

confidence: 95%

A Common Genetic Factor Underlies Genetic Risk for Gynaecological and Reproductive Disorders and Is Correlated with Risk to Depression

Kiewa,

Mortlock,

Meltzer-Brody

et al. 2023

Neuroendocrinology

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Introduction Sex steroid hormone fluctuations may underlie both reproductive disorders and sex difference in lifetime depression prevalence. Previous studies report high comorbidity among reproductive disorders and between reproductive disorders and depression. This study sought to assess the multivariate genetic architecture of reproductive disorders and their loading onto a common genetic factor, and investigated whether this latent factor shares a common genetic architecture with female depression, including perinatal depression (PND). Method Using UK Biobank and FinnGen data, genome-wide association meta-analyses were conducted for nine reproductive disorders, and genetic correlation between disorders estimated. Genomic Structural Equation Modelling identified a latent genetic factor underlying disorders, accounting for their significant genetic correlations. SNPs significantly associated with both latent factor and depression were identified. Results Excellent model fit existed between a latent factor underlying five reproductive disorders (2 (5)=6.4; AIC=26.4; CFI=1.00; SRMR=0.03) with high standardised loadings for menorrhagia (0.96, SE=0.05); ovarian cysts (0.94, SE=0.05); endometriosis (0.83, SE=0.05); menopausal symptoms (0.77, SE=0.10); and uterine fibroids (0.65, SE=0.05). This latent factor was genetically correlated with perinatal depression (PND) (rG = 0.37, SE=0.15, P=1.4e-03), depression in females only (rG=0.48, SE=0.06, P=7.2e-11) and depression in both males and females (MD) (rG=0.35, SE=0.03, P=1.8e-30), with its top locus associated with FSHB/ARL14EP (rs11031006; P=9.1e-33). SNPs intronic to ESR1, significantly associated with the latent factor, were also associated with PND, female depression, and MD. Discussion/Conclusion A common genetic factor, correlated with depression, underlies risk to reproductive disorders, with implications for etiology and treatment. Genetic variation in ESR1 is associated with reproductive disorders and depression, highlighting the importance of estrogen signalling to both reproductive and mental health.

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