Genome-wide gene expression changes in postpartum depression point towards an altered immune landscape

Grewen, Karen; Pearson, Brenda; Wani, Shivangi; Wallace, Leanne; Henders, Anjali K.; Binder, Elisabeth B.; Frøkjær, Vibe G.; Meltzer‐Brody, Samantha; Wray, Naomi R.; Stuebe, Alison M.

doi:10.1038/s41398-021-01270-5

Cited by 23 publications

(12 citation statements)

References 39 publications

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“…Three other transcriptome studies of PPD have been performed [ 22 – 24 ]. These previous studies were performed using whole blood and are independent of the current study, which allowed us to test whether our top bulk results overlap the most significant genes in the previous studies.…”

Section: Resultsmentioning

confidence: 99%

“…In this work, we performed the largest TWAS for PPD, using RNA-sequencing of whole blood, in a cohort of women six-weeks following childbirth. To date, three TWAS studies have been performed with sample sizes ranging from 6 to 15 cases and 10 to 122 controls [ 22 – 24 ]. Further, the analyses presented here are performed on a cell type-specific level.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptome-wide association study for postpartum depression implicates altered B-cell activation and insulin resistance

et al. 2022

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Postpartum depression (PPD) affects 1 in 7 women and has negative mental health consequences for both mother and child. However, the precise biological mechanisms behind the disorder are unknown. Therefore, we performed the largest transcriptome-wide association study (TWAS) for PPD (482 cases, 859 controls) to date using RNA-sequencing in whole blood and deconvoluted cell types. No transcriptional changes were observed in whole blood. B-cells showed a majority of transcriptome-wide significant results (891 transcripts representing 789 genes) with pathway analyses implicating altered B-cell activation and insulin resistance. Integration of other data types revealed cell type-specific DNA methylation loci and disease-associated eQTLs (deQTLs), but not hormones/neuropeptides (estradiol, progesterone, oxytocin, BDNF), serve as regulators for part of the transcriptional differences between cases and controls. Further, deQTLs were enriched for several brain region-specific eQTLs, but no overlap with MDD risk loci was observed. Altogether, our results constitute a convergence of evidence for pathways most affected in PPD with data across different biological mechanisms.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcriptome-wide association study for postpartum depression implicates altered B-cell activation and insulin resistance

et al. 2022

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“…Due to the profound changes that the immune system undergoes during pregnancy it has been suggested that inflammation could play a particularly important role in the development of depressive symptoms during this period [ 2 , 10 ]. Several recent studies have shown an association between levels of pro-inflammatory cytokines in the blood of pregnant women and depressive symptoms [ 11 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

Cytokines and tryptophan metabolites can predict depressive symptoms in pregnancy

et al. 2022

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Depression during and after pregnancy affects up to 20% of pregnant women, but the biological underpinnings remain incompletely understood. As pregnancy progresses, the immune system changes to facilitate fetal development, leading to distinct fluctuations in the production of pro-inflammatory factors and neuroactive tryptophan metabolites throughout the peripartum period. Therefore, it is possible that depression in pregnancy could constitute a specific type of inflammation-induced depression. Both inflammatory factors and kynurenine metabolites impact neuroinflammation and glutamatergic neurotransmission and can therefore affect mood and behavior. To determine whether cytokines and kynurenine metabolites can predict the development of depression in pregnancy, we analyzed blood samples and clinical symptoms in 114 women during each trimester and the postpartum. We analyzed plasma IL-1β, IL-2, -6, -8, -10, TNF, kynurenine, tryptophan, serotonin, kynurenic- quinolinic- and picolinic acids and used mixed-effects models to assess the association between biomarkers and depression severity. IL-1β and IL-6 levels associated positively with severity of depressive symptoms across pregnancy and the postpartum, and that the odds of experiencing significant depressive symptoms increased by >30% per median absolute deviation for both IL-1β and IL-6 (both P = 0.01). A combination of cytokines and kynurenine metabolites in the 2nd trimester had a >99% probability of accurately predicting 3rd trimester depression, with an ROC AUC > 0.8. Altogether, our work shows that cytokines and tryptophan metabolites can predict depression during pregnancy and could be useful as clinical markers of risk. Moreover, inflammation and kynurenine pathway enzymes should be considered possible therapeutic targets in peripartum depression.

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“…The increased capability of sequencing technology in recent years has also been able to provide valuable insight beyond cytokine expression at the gene expression and protein levels as measured in most other studies. A recent genome-wide association study ( 104 ) sought to identify genetic markers linked to PPD via RNA sequencing of whole blood samples. They found that immune biomarkers, such as genes responsible for encoding TNF-family receptors as well as A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs), were significantly upregulated in women showing depressive symptoms 2 months postpartum.…”

Section: Postpartum Depressionmentioning

confidence: 99%

Immune System Alterations and Postpartum Mental Illness: Evidence From Basic and Clinical Research

Dye

Lenz

Leuner

2022

Front. Glob. Womens Health

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The postpartum period is a time associated with high rates of depression and anxiety as well as greater risk for psychosis in some women. A growing number of studies point to aberrations in immune system function as contributing to postpartum mental illness. Here we review evidence from both clinical and animal models suggesting an immune component to postpartum depression, postpartum anxiety, and postpartum psychosis. Thus far, clinical data primarily highlights changes in peripheral cytokine signaling in disease etiology, while animal models have begun to provide insight into the immune environment of the maternal brain and how central inflammation may also be contributing to postpartum mental illnesses. Further research investigating peripheral and central immune function, along with neural and endocrine interactions, will be important in successfully developing novel prevention and treatment strategies for these serious disorders that impact a large portion of new mothers.

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Genome-wide gene expression changes in postpartum depression point towards an altered immune landscape

Cited by 23 publications

References 39 publications

Transcriptome-wide association study for postpartum depression implicates altered B-cell activation and insulin resistance

Transcriptome-wide association study for postpartum depression implicates altered B-cell activation and insulin resistance

Cytokines and tryptophan metabolites can predict depressive symptoms in pregnancy

Immune System Alterations and Postpartum Mental Illness: Evidence From Basic and Clinical Research

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