A study published in Molecular Psychiatry is the first to look at multiple levels of biology within women with postpartum depression (PPD) to see how women with the condition differ from those without it.
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.
“We don’t have PPD figured out,” said lead author Jerry Guintivano, Ph.D., assistant professor in the UNC Department of Psychiatry. “A lot of biological research focuses on candidate genes and hormones, and we do have a lead on some PPD-specific medications, but it’s important to take multiple avenues to target this condition. Not every manifestation of PPD is the same.”
That’s why Guintivano led a team of researchers from the UNC School of Medicine to conduct the largest transcriptome-wide association study for PPD to date. Previous studies have only analyzed whole blood samples. This study took a deeper look and examined the different components of blood.
They took blood samples from 1,500 racially and ethnically diverse women from across North Carolina who had given birth within the past six weeks, 482 of whom were diagnosed with PPD. Researchers used RNA sequencing, DNA genotyping, and assessment of DNA methylation – amounting to three levels of basic biology evaluation – to look for differences in components of the blood samples from women with PPD versus women without PPD.
They found that B-cells had significant differences in women with PPD. B-cells are an important part of the immune system. They become activated when their receptor recognizes an antigen and binds to it. Activated B-cells then produce antibodies, and also secrete pro- and anti-inflammatory factors.
“There’s a really delicate interplay of the immune system during pregnancy,” Guintivano said. “It has to prevent infection from a cold, and it also has to finely tune itself so it doesn’t recognize the fetus as a foreign body and attack it. Then in the postpartum period, all these hormones and pathways reset to get back to pre-pregnancy.”
In women with PPD, the UNC researchers found thousands of individual B-cell transcripts that were different from women without PPD, regulated in part by genetic variants and DNA methylation. To confirm those findings they conducted pathway analysis, which implicated altered B-cell activation and insulin resistance.
“This is really just the first step in a long line of research that now needs to be done,” Guintivano said. “This is the biggest study of its type but we still don’t know why B-cells are changing. Are they reflecting another change in the body that is caused by or causes PPD? What is driving this B-cell behavior?”
Guintivano says their next step is to conduct a longitudinal study that tracks women across a longer period of time to see how B-cells change through pregnancy and into the postpartum period. He says none of this research would be possible without many women being dedicated to research on PPD.
“The women who participated in this study are new moms who came in during a very critical time when their babies are weeks old to participate in research to help other women, Guintivano said. “I want to thank them for that. We want to do their contributions justice with our research.”
To generate novel hypotheses for PPD disease pathology, we studied the biological underpinnings of PPD in a large cohort of women six weeks after childbirth. Results showed cell type-specific transcriptional differences associated with PPD, with a majority of the changes seen in B-cells. Furthermore, these associations were significantly overrepresented in multiple sets of pathways. These pathways reflected the significant effects of SNPs regulating the PPD-associated transcriptional changes. This constitutes a convergence of evidence with data from two different biological mechanisms.
Pregnancy is characterized by substantial changes in multiple physiological systems. Failure to return to pre-pregnancy levels during the postpartum period may contribute to PPD symptoms, making these systems candidate mechanisms for PPD. Our association and pathway results implicate two, potentially co-occurring, such mechanisms: B-cell activation and insulin resistance (IR). In addition to showing pregnancy-related changes, both mechanisms have previously been linked to depression [39,40,41,42,43,44].
Our results specifically implicate B-cell activation (Fig. 2, cluster 10), which plays a critical role in the immune system. B-cells becomes activated when their receptor recognizes an antigen and binds to it. Activated B-cells then produce antibodies, along with secreting pro- and anti-inflammatory factors. During pregnancy, B-cells undergo dynamic changes as the maternal immune system has to balance tolerance of the foreign‐growing fetus with maintaining vigilance against pathogens [45, 46]. Thus, B-cell concentrations are significantly lower during the third trimester and immediately following delivery compared to non-pregnant women, but levels typically return to those seen in non-pregnant women by six-weeks postpartum .
A growing body of evidence suggests that inflammatory processes may play a significant role in PPD [24, 48,49,50]. However, the specific role of B-cells has yet to be elucidated. Recent work has shown an increase in B-cell densities in the brains of those with mood disorders compared to controls . Furthermore, in whole blood, altered B-cell homeostasis was observed in those with MDD compared to controls [40, 41]. A possible mechanism contributing to increased B-cell activation could be related to autoimmunity . Depression is often co-morbid with autoimmune disease; risk of depression is 1.25–3.56 times higher in people with autoimmune disease than without [52,53,54]. Additionally, a feature of many autoimmune disorders is a loss of B-cell tolerance coinciding with the inappropriate production of autoantibodies [51, 55]. Thus, an aberrant autoimmune response could potentially contribute to PPD.
Further, we did not observe significant differences in B-cell proportions between cases and controls (p-value = 0.78). As multiple subtypes of B-cells exist, it may be that we did not observe differences in overall B-cell proportions but there may be differences in more specific B-cell subsets.
Not only do we observe a pathway cluster, composed of 12 pathways, directly related to B-cell activation (cluster 10), we see multiple pathway clusters associated with cellular metabolism, which supports our hypothesis of B-cell activation. Activation initializes cellular reprogramming of quiescent naïve B-cells to drive re-entry into the cell cycle . This rapid expansion requires the production of biomolecules (lipids, proteins, nucleotides in clusters 2, 5, 6, and 9) at an increased rate. Additionally, work in mice has shown that B-cell activation results in increased glucose uptake (cluster 2) and mitochondrial remodeling (cluster 8) . Upon B-cell activation, not only is there a slew of metabolic changes, but there are changes to the cellular structure (cluster 1). Antigen binding triggers substantial remodeling of the cell cytoskeleton, which induces cell spreading, the formation of the immune synapse, and the gathering of antigen for endocytosis . Additionally, apoptosis is a carefully regulated process through the lifecycle of B-cells. Disruptions to apoptotic pathways (cluster 8) affect multiple processes including homeostasis, quality control of the antibody response, and tolerance .
The second implicated mechanism, insulin resistance (IR), is supported by several factors. Insulin promotes the absorption of excess blood glucose into other tissues for energy storage. IR occurs when cells become insensitive to the effects of insulin leading to a buildup of blood glucose and insulin. Starting in the second trimester of pregnancy, insulin sensitivity is progressively reduced as much as 60–80% . This coincides with steady increases in insulin . These changes serve as a physiological adaptation of the mother to ensure adequate carbohydrate supply for the rapidly growing fetus . After delivery, insulin returns to pre-pregnancy levels [62,63,64].
IR is a risk factor for depression. Rodent studies have shown that brain IR alters dopamine turnover and induces anxiety and depressive-like behaviors in mice . In humans, greater glycemic variability has been associated with negative moods . IR typically predates the development of diabetes. A meta-analysis of 27 studies demonstrated that depression is significantly associated with hyperglycemia for both type 1 and type 2 diabetes . Studies further suggest that insulin-sensitizing agents could play a significant role in the treatment of major depression, particularly in patients with documented IR [68, 69]. Pregnancy is known to increase the risk of developing Type 2 diabetes after giving birth . Furthermore, pre-pregnancy or gestational diabetes was independently associated with perinatal depression, including new onset of PPD [71,72,73].
We tested whether genes implicated by our top results were significantly overrepresented for genes related to A1C  and IR  in whole blood. Hemoglobin A1C levels are measure of a person’s blood sugar levels over the past three months and are highly correlated with measures of IR . We found the top 5% of our whole blood findings for PPD were enriched for the top 5% of associations with A1C (p-value = 4.79 × 10−7) and IR (p-values = 0.04). Databases can not directly implicate IR as such a pathway does not exist. IR is a disorder characterized by disruptions of multiple biological functions. However, IR can be implicated by nearly all clusters in our pathway analyses (Fig. 2). With the evidence linking IR and B-cells [77, 78], it is reasonable to observe a signature of IR in B-cells. For example, B-cells contribute to the development of IR (cluster 10). These cells can promote IR through T-cell modulation and production of pathogenic antibodies [77, 78]. Insulin signaling regulates diverse cellular functions including metabolic pathways, apoptosis, mitogenesis, and membrane trafficking through protein kinases (cluster 1) [79, 80]. Insulin directly affects glucose metabolic processes (cluster 2). Circulating levels of purines (cluster 5) [81, 82], amino acids, and fatty acids (cluster 6) [83, 84] are also associated with IR. The administration of carboxylic acids (cluster 6) improved glycemic control, potentially by reducing IR . IR may lead to inadequate intracellular glucose potentially leading to apoptosis and intracellular starvation (cluster 7 and 8) . Wnt signaling (cluster 9) is involved in the regulation of glucose homeostasis in multiple organs, particularly in insulin-responsive tissues .
A number of limitations of the present study should be mentioned. While we studied blood, the pathogenic processes for PPD most likely manifest in the brain. It is likely that in studying blood, other possible PPD-related mechanisms might have been missed. However, there is cross-talk between the two tissues across the blood-brain barrier . This would allow altered B-cell activation and IR to affect the brain and be observed in our study. Furthermore, we observed deQTLs that affect genes in both blood and brain, specifically in brain regions implicated in mood disorders (e.g., hippocampus, cingulate cortex, frontal cortex). These deQTLs can be studied in model systems for functional follow-up to evaluate causality and their downstream biological effects . Additionally, the B-cell activation and IR hypotheses for PPD requires further validation through direct measurements in PPD cases versus controls.
In conclusion, we have performed the largest and most comprehensive biological interrogation of PPD, to date. Our results suggest that PPD is associated with an increase in B-cell activation, a finding previously unreported in the literature. While we do not know the precise mechanisms behind this increase in B-cell activation, we hypothesize it could be due to co-occurring dysregulation in IR. Additionally, we identified genetic variants, deQTLs, that regulate, in part, the transcriptional differences between cases and controls. Our findings require further validation and follow-up studies. However, these novel hypotheses for PPD provide promising avenues for future research.
reference link: https://www.nature.com/articles/s41380-022-01525-7
More information: Jerry Guintivano et al, Transcriptome-wide association study for postpartum depression implicates altered B-cell activation and insulin resistance, Molecular Psychiatry (2022). DOI: 10.1038/s41380-022-01525-7