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

ABSTRACT: 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.

SUBMITTER: Guintivano J

PROVIDER: S-EPMC9156403 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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

Guintivano Jerry J Aberg Karolina A KA Clark Shaunna L SL Rubinow David R DR Sullivan Patrick F PF Meltzer-Brody Samantha S van den Oord Edwin J C G EJCG

Molecular psychiatry 20220401 6

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 ...[more]

PMID: 35365803

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Project description:BackgroundDepression is a common psychiatric illness and global public health problem. However, our limited understanding of the biological basis of depression has hindered the development of novel treatments and interventions.MethodsTo identify new candidate genes for therapeutic development, we examined single-nucleus RNA sequencing (snucRNAseq) data from the dorsolateral prefrontal cortex (N=424) in relation to ante-mortem depressive symptoms. To complement these direct analyses, we also used genome-wide association study (GWAS) results for depression (N=500,199) along with genetic tools for inferring the expression of 22,159 genes in 7 cell types and 55 cell subtypes to perform transcriptome-wide association studies (TWAS) of depression followed by Mendelian randomization (MR).ResultsOur single-nucleus TWAS analysis identified 71 causal genes in depression that have a role in specific neocortical cell subtypes; 59 of 71 genes were novel compared to previous studies. Depression TWAS genes showed a cell type specific pattern, with the greatest enrichment being in both excitatory and inhibitory neurons as well as astrocytes. Gene expression in different neuron subtypes have different directions of effect on depression risk. Compared to lower genetically correlated traits (e.g. body mass index) with depression, higher correlated traits (e.g., neuroticism) have more common TWAS genes with depression. In parallel, we performed differential gene expression analysis in relation to depression in 55 cortical cell subtypes, and we found that genes such as ANKRD36, MADD, TAOK3, SCAI and CHUK are associated with depression in specific cell subtypes.ConclusionsThese two sets of analyses illustrate the utility of large snucRNAseq data to uncover both genes whose expression is altered in specific cell subtypes in the context of depression and to enhance the interpretation of well-powered GWAS so that we can prioritize specific susceptibility genes for further analysis and therapeutic development.

Project description:Maternal postpartum depression (PPD) is a significant public health concern due to the severe negative impact on maternal and child health and well-being. In this study, we aimed to identify genes associated with PPD. To do this, we investigated genome-wide gene expression profiles of pregnant women during their third trimester of pregnancy and tested the association of gene expression with perinatal depressive symptoms. A total of 137 women from a cohort from the University of North Carolina, USA were assessed. The main phenotypes analysed were Edinburgh Postnatal Depression Scale (EPDS) scores at 2 months postpartum and PPD (binary yes/no) based on an EPDS cutoff of 10. Illumina NextSeq500/550 transcriptomic sequencing from whole blood was analysed using the edgeR package. We identified 71 genes significantly associated with postpartum depression scores at 2 months, after correction for multiple testing at 5% FDR. These included several interesting candidates including TNFRSF17, previously reported to be significantly upregulated in women with PPD and MMP8, a matrix metalloproteinase gene, associated with depression in a genome-wide association study. Functional annotation of differentially expressed genes revealed an enrichment of immune response-related biological processes. Additional analysis of genes associated with changes in depressive symptoms from recruitment to 2 months postpartum identified 66 genes significant at an FDR of 5%. Of these genes, 33 genes were also associated with depressive symptoms at 2 months postpartum. Comparing the results with previous studies, we observed that 15.4% of genes associated with PPD in this study overlapped with 700 core maternal genes that showed significant gene expression changes across multiple brain regions (P = 7.9e-05) and 29-53% of the genes were also associated with estradiol changes in a pharmacological model of depression (P values range = 1.2e-4-2.1e-14). In conclusion, we identified novel genes and validated genes previously associated with oestrogen sensitivity in PPD. These results point towards the role of an altered immune transcriptomic landscape as a vulnerability factor for PPD.

Project description:BackgroundDepression is a disabling and highly prevalent condition where genetic and epigenetic, such as DNA methylation (DNAm), differences contribute to disease risk. DNA methylation is influenced by genetic variation but the association between polygenic risk of depression and DNA methylation is unknown.MethodsWe investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N = 8898, mean age = 49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in the Avon Longitudinal Study of Parents and Children (ALSPAC) (Ncombined = 2049, mean age = 79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N = 423, mean age = 17.1 years). Gene ontology analysis was conducted for the cytosine-guanine dinucleotide (CpG) probes significantly associated with depression PRS, followed by Mendelian randomisation (MR) analysis to infer the causal relationship between depression and DNAm.ResultsWidespread associations (NCpG = 71, pBonferroni < 0.05, p < 6.3 × 10-8) were found between PRS constructed using genetic risk variants for depression and DNAm in CpG probes that localised to genes involved in immune responses and neural development. The effect sizes for the significant associations were highly correlated between the discovery and replication samples in adults (r = 0.79) and in adolescents (r = 0.82). Gene Ontology analysis showed that significant CpG probes are enriched in immunological processes in the human leukocyte antigen system. Additional MWAS was conducted for each lead genetic risk variant. Over 47.9% of the independent genetic risk variants included in the PRS showed associations with DNAm in CpG probes located in both the same (cis) and distal (trans) locations to the genetic loci (pBonferroni < 0.045). Subsequent MR analysis showed that there are a greater number of causal effects found from DNAm to depression than vice versa (DNAm to depression: pFDR ranged from 0.024 to 7.45 × 10-30; depression to DNAm: pFDR ranged from 0.028 to 0.003).ConclusionsPRS for depression, especially those constructed from genome-wide significant genetic risk variants, showed methylome-wide differences associated with immune responses. Findings from MR analysis provided evidence for causal effect of DNAm to depression.

Project description:Conflicting results of Chinese traditional postpartum practices have aroused concerns over their health effects. The role of postpartum practices in postpartum depression (PPD) is still a matter of discussion, especially from a dietary practice point of view. The current study was designed to (1) explore the association between postpartum practices and PPD, (2) to identify the dietary pattern related to PPD, and (3) to identify the possible pathways among postpartum practices and PPD. This study is part of the YI Study, which was a cross-sectional study conducted in 10 cities in China. Data for 955 postpartum women were used in the current analysis. The Edinburgh Postnatal Depression Scale (EPDS-10) was used to evaluate PPD with a cutoff value of 9. Postpartum practice was based on the participants' self-reported practices. Individual practices were recorded and categorized as dietary and non-dietary practices. The dietary pattern was identified based on the food intake frequencies of 25 food groups using the method of reduced rank regression. Structural equation modeling was used to explore the potential pathways between postpartum practices and PPD. The current study observed significant associations between postpartum practices and PPD (Adjusted OR = 1.41, 95% CI: 1.04-1.90). A similar trend was also found between dietary postpartum practices and PPD (Adjusted OR = 1.39, 95%CI: 1.03-1.88) but not for non-dietary practices and PPD (Adjusted OR = 1.26, 95%CI: 0.92-1.75). A PPD-related dietary pattern was identified with the characteristics of a high intake of meat and eggs and a lower intake of vegetables, mushrooms, and nuts. This dietary pattern was significantly associated with a higher chance of adhering to postpartum practice (Adjusted OR = 1.26, 95% CI: 1.10-1.44). Based on the pathway analysis, this study also observed the association between postpartum practices and PPD, and the association between dietary practices and PPD were both mediated by sleep quality. In conclusion, this study demonstrated that a substantial proportion of women in modern China experience traditional postpartum Chinese practices and that either overall or dietary-related postpartum practices are associated with a higher risk of PPD. The current dietary practices in postpartum rituals may play an important role in developing PPD. A culturally embedded, science-based dietary guideline is required to help women to achieve both physical and psychological health in the postpartum period.

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

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

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