RESUMO
Background: We examined differences in DNA methylation patterns in the NR3C1 and FKBP5 genes in relation to personality vulnerability to depression, resilience, and perinatal depressive symptoms, whilst also considering possible moderating effects of childhood traumatic events. Methods: N = 160 perinatal women were assessed at late pregnancy and 1 year postpartum for personality vulnerability to depression, resilience, depressive symptoms, and childhood traumatic events with self-reported questionnaires. NR3C1 and FKBP5 methylation markers were analyzed via sodium bisulfite sequencing. Associations of methylation markers with the above mentioned variables were tested using multivariable regressions. Results: NR3C1 methylation at CpGs 1, 4 and average methylation sites were negatively associated with resilience; NR3C1 methylation at CpG 2 was positively associated with postpartum depressive symptoms; methylation at CpG 4 was positively associated with prenatal depressive symptoms. The interaction between current distress due to interpersonal traumatic events and NR3C1 CpG sites in relation to personality vulnerability was significant on CpG sites 3 and 4, whereas the interaction between current distress due to total traumatic events and NR3C1 in relation to personality vulnerability was significant on CpG site 2. FKBP5 showed no significant associations with the outcomes. Conclusions: This study identified associations between NR3C1 methylation and resilience as well as perinatal depressive symptoms. Interestingly, an interaction between early trauma and personality vulnerability was noted. Our findings on these specific DNA methylation markers may, if replicated and integrated into risk prediction models, contribute to early diagnosis of mothers at risk, targeted health promotion, and early interventions.
Assuntos
Metilação de DNA , Depressão , Epigênese Genética , Receptores de Glucocorticoides , Resiliência Psicológica , Proteínas de Ligação a Tacrolimo , Humanos , Feminino , Proteínas de Ligação a Tacrolimo/genética , Adulto , Gravidez , Receptores de Glucocorticoides/genética , Depressão/genética , Personalidade/genética , Ilhas de CpG , Depressão Pós-Parto/genética , Inquéritos e Questionários , BiomarcadoresRESUMO
BACKGROUNDS: Empirical investigations have shown an association between gut microbiota and postpartum depression (PPD); nevertheless, the precise cause-and-effect relationship between these two variables remains ambiguous. This research aimed to examine the possible reciprocal causal relationship between the gut microbiota and PPD. METHODS: In this work, we used Mendelian randomization (MR) to analyze the relationship between the gut microbiota (n = 18,340) and PPD (n = 67,205). We obtained the relevant SNPs from publicly accessible genome-wide association studies (GWAS). The SNP estimations were combined by the inverse-variance weighted (IVW) method, including sensitivity analyses such as weighted median, MR Egger, and MR Pleiotropy Residual Sum and Outlier (PRESSO). RESULTS: We have identified strong correlations between six bacterial characteristics and the likelihood of developing PPD. Our research revealed that the genus Ruminococcaceae UCG010, the family Veillonellaceae, and the class Clostridia had a beneficial effect on preventing PPD. The class Alphaproteobacteria, genus Slackia, and order NB1n were found to have a significant negative impact on PPD. The sensitivity studies conducted on these bacterial features consistently confirmed these finding. LIMITATIONS: It is crucial to acknowledge that our study was conducted just within a European society, which may restrict its applicability to other groups. CONCLUSIONS: The findings from our MR investigation indicate a potential causal relationship between certain kinds of gut bacteria and PPD. Additional investigation is required to elucidate the influence of gut microbiota on the advancement of PPD.
Assuntos
Depressão Pós-Parto , Microbioma Gastrointestinal , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Humanos , Microbioma Gastrointestinal/genética , Feminino , Depressão Pós-Parto/genética , Depressão Pós-Parto/microbiologiaRESUMO
BACKGROUND: This study aimed to explore the causal relationship between age at first birth (AFB) and depression. METHODS: Using the univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) methods to examine the potential correlation between age at first birth (AFB) and major depressive disorder and postpartum depression. A public database was used to obtain the genome-wide association studies (GWAS) summary data. We put inverse-variance-weighted (IVW) as the primary method in Mendelian randomization (MR) analysis and used sensitivity analysis to confirm the robustness of our result. RESULTS: We found a significant causal association between AFB and major depressive disorder by using the IVW algorithm (odd ratio [OR] 0.826; 95% confidence interval [CI] 0.793 - 0.861; P = 4.51 × 10- 20). MR-Egger, weighted median, simple mode and weighted mode method concluded the same result (P < 0.05). During the sensitivity analysis, the heterogeneity test (Q-value = 55.061, df = 48, P = 2.81 × 10- 01, I2 = 12.82%) and the leave-one-out plot analysis confirmed the stability of the results. The outcomes of the pleiotropy test (MR-Egger intercept = 8.932 × 10- 3. SE = 6.909 × 10- 3. P = 2.02 × 10- 01) and MR_PRESSO global test (P = 2.03 × 10- 01) indicated there is no pleiotropy. CONCLUSION: There is solid evidence that a higher age at first birth is associated with a lower risk of major depressive disorder.
Assuntos
Transtorno Depressivo Maior , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Humanos , Feminino , Transtorno Depressivo Maior/genética , Depressão Pós-Parto/genética , Idade Materna , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Background: Postpartum depression (PPD) is a common complication of pregnancy that imposes a heavy health and economic burden on individuals, families and society. The etiology of PPD is complex and incompletely defined, and recent studies have identified an important role for gut microbiota (GM) and their metabolites in neurological disorders. However, fewer studies on GM and PPD are available and have not yielded uniform results. Methods: Instrumental variables for GM and blood metabolites were obtained from the MiBioGen consortium and metabolomics GWAS server. Single nucleotide polymorphisms (SNPs) associated with PPD phenotypes were obtained from the FinnGen consortium. Inverse variance weighted (IVW), weighted median, weighted mode, and MR-Egger methods were used to assess causal effects. Inverse MR analysis and sensitivity analysis were also utilized to improve the stability of the results. Results: In this study, 5 intestinal species and 24 blood metabolites causally associated with PPD were identified using MR analysis. In addition, MR analysis showed that Prevotellaceae and Bifidobacteria may reduce the risk of PPD by elevating Xanthine and 1-arachidonoylglycerophosphoinositol (LysoPI) levels. Conclusions: This study identified GM and blood metabolites causally associated with PPD. The results of this study may provide a theoretical basis for the discovery of PPD-related biomarkers and the treatment of the disease by regulating the gut microenvironment.
Assuntos
Depressão Pós-Parto , Microbioma Gastrointestinal , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Humanos , Depressão Pós-Parto/sangue , Depressão Pós-Parto/genética , Microbioma Gastrointestinal/genética , Feminino , Estudo de Associação Genômica Ampla , Metabolômica , GravidezRESUMO
BACKGROUND: Postpartum depression is a complex mental health condition that often occurs after childbirth and is characterized by persistent sadness, anxiety, and fatigue. Recent research suggests a metabolic component to the disorder. This study aims to investigate the causal relationship between blood metabolites and postpartum depression using mendelian randomization (MR). METHODS: This study used a bi-directional MR framework to investigate the causal relationship between 1,400 metabolic biomarkers and postpartum depression. We used two specific genome-wide association studies datasets: one with single nucleotide polymorphisms data from mothers diagnosed with postpartum depression and another with blood metabolite data, both of which focused on people of European ancestry. Genetic variants were chosen as instrumental variables from both datasets using strict criteria to improve the robustness of the MR analysis. The combination of these datasets enabled a thorough examination of genetic influences on metabolic profiles associated with postpartum depression. Statistical analyses were conducted using techniques such as inverse variance weighting, weighted median, and model-based estimation, which enabled rigorous causal inference from the observed associations. postpartum depression was defined using endpoint definitions approved by the FinnGen study's clinical expert groups, which included leading experts in their respective medical fields. RESULTS: The MR analysis identified seven metabolites that could be linked to postpartum depression. Out of these, one metabolite was found to be protective, while six were associated with an increased risk of developing the condition. The results were consistent across multiple MR methods, indicating a significant correlation. CONCLUSIONS: This study emphasizes the potential of metabolomics for understanding postpartum depression. The discovery of specific metabolites associated with the condition sheds new insights on its pathophysiology and opens up possibilities for future research into targeted treatment strategies.
Assuntos
Depressão Pós-Parto , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Humanos , Depressão Pós-Parto/genética , Depressão Pós-Parto/sangue , Feminino , Metabolômica , Biomarcadores/sangue , Adulto , População Branca/genética , GravidezRESUMO
Major depressive disorder (MDD) is a clinically and genetically heterogeneous disorder. To reduce heterogeneity, large-scale genome-wide association studies have recently identified genome-wide significant loci associated with seven MDD subtypes. However, it was unclear in which tissues the genes near those loci are specifically expressed. We investigated whether genes related to specific MDD subtypes would be preferably expressed in a specific tissue. At 14 novel subtype-specific loci related to seven MDD subtypes-(1) non-atypical-like features MDD, (2) early-onset MDD, (3) recurrent MDD, (4) MDD with suicidal thoughts, (5) MDD without suicidal thoughts, (6) MDD with moderate impairment, and (7) postpartum depression, we investigated whether 22 genome-wide significant genetic variant-mapped genes were tissue-specifically expressed in brain, female reproductive, male specific, cardiovascular, gastrointestinal, or urinary tissues in the Genotype-Tissue Expression (GTEx) subjects (n ≤ 948). To confirm the tissue-specific expression in the GTEx, we used independent Human Protein Atlas (HPA) RNA-seq subjects (n ≤ 95). Of 22 genes, nine and five genes were tissue-specifically expressed in brain and female reproductive tissues, respectively (p < 2.27 × 10-3). RTN1, ERBB4, and AMIGO1 related to early-onset MDD, recurrent MDD, or MDD with suicidal thoughts were highly expressed in brain tissues (d = 1.19-2.71), while OAS1, LRRC9, DHRS7, PSMA5, SYPL2, and GULP1 related to non-atypical-like features MDD, early-onset MDD, MDD with suicidal thoughts, or postpartum depression were expressed at low levels in brain tissues (d = -0.17--1.48). DFNA5, CTBP2, PCNX4, SDCCAG8, and GULP1, which are related to early-onset MDD, MDD with moderate impairment, or postpartum depression, were highly expressed in female reproductive tissues (d = 0.80-2.08). Brain and female reproductive tissue-specific expression was confirmed in the HPA RNA-seq subjects. Our findings suggest that brain and female reproductive tissue-specific expression might contribute to the pathogenesis of MDD subtypes.
Assuntos
Transtorno Depressivo Maior , Estudo de Associação Genômica Ampla , Humanos , Transtorno Depressivo Maior/genética , Feminino , Masculino , Adulto , Encéfalo/metabolismo , Expressão Gênica , Especificidade de Órgãos , Ideação Suicida , Pessoa de Meia-Idade , Depressão Pós-Parto/genéticaRESUMO
PURPOSE: Postpartum depression (PPD) brings adverse and serious consequences to both new parents and newborns. Neuroticism affects PPD, which remains controversial for confounding factors and reverse causality in cross-sectional research. Therefore, mendelian randomization (MR) study has been adopted to investigate their causal relationship. METHODS: This study utilized large-scale genome-wide association study genetic pooled data from three major databases: the United Kingdom Biobank, the European Bioinformatics Institute, and the FinnGen databases. The causal analysis methods used inverse variance weighting (IVW). The weighted median, MR-Egger method, MR-PRESSO test, and the leave-one-out sensitivity test have been used to examine the results' robustness, heterogeneity, and horizontal pleiotropy. The fixed effect model yielded the results of meta-analysis. RESULTS: In the IVW model, a meta-analysis of the MR study showed that neuroticism increased the risk of PPD (OR, 1.17; 95% CI, 1.11-1.25, p < 0.01). Reverse analysis showed that PPD could not genetically predict neuroticism. There was no significant heterogeneity or horizontal pleiotropy bias in this result. CONCLUSION: Our study suggests neuroticism is the risk factor for PPD from a gene perspective and PPD is not the risk factor for neuroticism. This finding may provide new insights into prevention and intervention strategies for PPD according to early detection of neuroticism.
Assuntos
Depressão Pós-Parto , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Neuroticismo , Humanos , Depressão Pós-Parto/genética , Depressão Pós-Parto/epidemiologia , Feminino , Fatores de Risco , Adulto , Reino Unido/epidemiologia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , CausalidadeRESUMO
The absence of non-invasive tests that can monitor the status of the brain is a major obstacle for psychiatric care. In order to address this need, we assessed the feasibility of using tissue-specific gene expression to determine the origin of extracellular vesicle (EV) mRNAs in peripheral blood. Using the placenta as a model, we discovered that 26 messenger RNAs that are specifically expressed in the placenta are present in EVs circulating in maternal blood. Twenty-three of these transcripts were either exclusively or highly expressed in maternal blood during pregnancy only and not in the postpartum period, verifying the feasibility of using tissue-specific gene expression to infer the tissue of origin for EV mRNAs. Using the same bioinformatic approach, which provides better specificity than isolating L1 cell-adhesion molecule containing EVs, we discovered that 181 mRNAs that are specifically expressed in the female brain are also present in EVs circulating in maternal blood. Gene set enrichment analysis revealed that these transcripts, which are involved in synaptic functions and myelination, are enriched for genes implicated in mood disorders, schizophrenia, and substance use disorders. The EV mRNA levels of 13 of these female brain-specific transcripts are associated with postpartum depression (adjusted p-vals = 3 × 10-5 to 0.08), raising the possibility that they can be used to infer the state of the brain. In order to determine the extent to which EV mRNAs reflect transcription in the brain, we compared mRNAs isolated from cells and EVs in an iPSC-derived brain microphysiological system differentiated for 3 and 9 weeks. We discovered that, although cellular and extracellular mRNA levels are not identical, they do correlate, and it is possible to extrapolate cellular RNA expression changes in the brain via EV mRNA levels. Our findings bring EV mRNAs to the forefront of peripheral biomarker development efforts in psychiatric diseases by demonstrating the feasibility of inferring transcriptional changes in the brain via blood EV mRNA levels.
Assuntos
Biomarcadores , Encéfalo , Vesículas Extracelulares , RNA Mensageiro , Feminino , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Humanos , RNA Mensageiro/metabolismo , Encéfalo/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Gravidez , Placenta/metabolismo , Expressão Gênica/genética , Adulto , Depressão Pós-Parto/genética , Depressão Pós-Parto/metabolismoRESUMO
BACKGROUND: Postpartum depression (PPD), a prevalent social-mental condition, impacts the mother and the newborn and several facets of their lives. It has been suggested that insomnia is related to both the occurrence and progression of PPD. However, because of lingering confounding and bias, it is impossible to determine the cause of this connection using observational analysis. In this study, we evaluate the causal importance of insomnia on postpartum depression using Mendelian randomization (MR). METHODS: Utilizing summary data from genome-wide association studies (GWAS), a two-sample MR study was conducted. A GWAS dataset of IEU study of the United Kingdom Biobank phenotypes comprising 462,341 people of European heritage yielded 38 single-nucleotide polymorphisms (SNPs) for insomnia. The PPD data were provided by the FinnGen project and comprised 7604 cases and 59,601 controls. Inverse variance weighting (IVW) was utilized for the primary MR analysis, with weighted median and MR-Egger as sensitivity analyses. RESULTS: As a result, we found that genetically predicted insomnia was positively associated with postpartum depression. The odds ratios (OR) of PPD were 1.849 (95% (confidence interval) CI 1.011-3.381; p = 0.046). CONCLUSION: For the first time, the causative role of sleeplessness for postpartum depression has been extensively evaluated in the current two-sample MR investigation. Our findings show that insomnia and PPD are related causally.
Assuntos
Depressão Pós-Parto , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Distúrbios do Início e da Manutenção do Sono , Humanos , Depressão Pós-Parto/genética , Depressão Pós-Parto/epidemiologia , Feminino , Distúrbios do Início e da Manutenção do Sono/genética , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Reino Unido/epidemiologiaRESUMO
It remains inconclusive whether postpartum depression (PPD) and depression with onset outside the postpartum period (MDD) are genetically distinct disorders. We aimed to investigate whether polygenic risk scores (PGSs) for major mental disorders differ between PPD cases and MDD cases in a nested case-control study of 50,057 women born from 1981 to 1997 in the iPSYCH2015 sample in Demark. We identified 333 women with first-onset postpartum depression (PPD group), who were matched with 993 women with first-onset depression diagnosed outside of postpartum (MDD group), and 999 female population controls. Data on genetics and depressive disorders were retrieved from neonatal biobanks and the Psychiatric Central Research Register. PGSs were calculated from both individual-level genetic data and meta-analysis summary statistics from the Psychiatric Genomics Consortium. Conditional logistic regression was used to calculate the odds ratio (OR), accounting for the selection-related reproductive behavior. After adjustment for covariates, higher PGSs for severe mental disorders were associated with increased ORs of both PPD and MDD. Compared with MDD cases, MDD PGS and attention-deficit/hyperactivity disorder PGS were marginally but not statistically higher for PPD cases, with the OR of PPD versus MDD being 1.12 (95% CI: 0 .97-1.29) and 1.11 (0.97-1.27) per-standard deviation increase, respectively. The ORs of PPD versus MDD did not statistically differ by PGSs of bipolar disorder, schizophrenia, or autism spectrum disorder. Our findings suggest that relying on PGS data, there was no clear evidence of distinct genetic make-up of women with depression occurring during or outside postpartum, after taking the selection-related reproductive behavior into account.
Assuntos
Transtorno do Espectro Autista , Depressão Pós-Parto , Transtorno Depressivo Maior , Recém-Nascido , Humanos , Feminino , Depressão Pós-Parto/epidemiologia , Depressão Pós-Parto/genética , Estudos de Casos e Controles , Transtorno Depressivo Maior/diagnóstico , Período Pós-Parto/psicologia , Fatores de RiscoRESUMO
OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).
Assuntos
Transtorno Bipolar , Depressão Pós-Parto , Transtorno Depressivo Maior , Feminino , Humanos , Animais , Camundongos , Transtorno Depressivo Maior/genética , Estudo de Associação Genômica Ampla , Depressão Pós-Parto/genética , Predisposição Genética para Doença , Transtorno Bipolar/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Pregnancy and the post-partum period are associated with substantial fluctuations in hormone levels and are frequently associated with significant stress. Many individuals also experience affective disturbances during the peripartum period, including anxiety, the 'baby blues,' and post-partum depression. However, the extent to which these affective changes result from rapidly altering hormone levels, increased stress, or the combination of both remains largely unknown. The current study sought to evaluate the consequences of pregnancy-like hormonal changes on behavior and gene expression in c57BL/6 mice in the absence of stress using a hormone-simulated pregnancy model. Our results reveal that animals receiving hormone injections to simulate the high levels of estrogen observed in late pregnancy and animals withdrawn from estrogen to mimic the rapid decline in this hormone following parturition both exhibit increased anxiety-like behavior compared to ovariectomized controls in the novel open field test. However, no other significant anxiety- or depression-like alterations were observed in either hormone-treated group compared to ovariectomized controls. Both hormone administration and estrogen withdrawal were shown to induce several significant alterations in gene expression in the bed nucleus of the stria terminalis and the paraventricular nucleus of the hypothalamus. In contrast to the estrogen withdrawal hypothesis of post-partum depression, our results suggest that this method estrogen withdrawal following hormone-simulated pregnancy in the absence of stress does not induce phenotypes consistent with post-partum depression in c57BL/6 mice. However, given that estrogen withdrawal does lead to significant gene expression changes in two stress-sensitive brain regions, it remains possible that estrogen withdrawal could still contribute to affective dysregulation in the peri-partum period by influencing susceptibility to stress. Future research is required to evaluate this possibility.
Assuntos
Depressão Pós-Parto , Humanos , Feminino , Camundongos , Gravidez , Animais , Depressão Pós-Parto/induzido quimicamente , Depressão Pós-Parto/genética , Depressão/induzido quimicamente , Estrogênios/metabolismo , Período Pós-Parto/psicologia , Expressão GênicaRESUMO
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.
Assuntos
Depressão Pós-Parto , Pregnanolona , Humanos , Feminino , Pregnanolona/farmacologia , Pregnanolona/metabolismo , Pregnanolona/uso terapêutico , Depressão Pós-Parto/tratamento farmacológico , Depressão Pós-Parto/genética , Depressão Pós-Parto/metabolismo , Transcriptoma/genética , Dimetil Sulfóxido , Antidepressivos/farmacologia , Antidepressivos/uso terapêuticoRESUMO
BACKGROUND: Prenatal and postnatal depression potentially have severe consequences, but we do not know to what extent they have the same etiological factors. Genetically informative designs yield insight into common etiology between pre- and postnatal depression and inform on potential prevention and intervention efforts. This study evaluates the overlap in genetic and environmental factors in pre- and postnatal depression symptoms. METHODS: We conducted univariate and bivariate modeling, using a quantitative, extended twin study. The sample was a subsample of the MoBa prospective pregnancy cohort study in 6039 pairs of related women. Measurement was conducted at week 30 of pregnancy and 6 months following delivery, using a self-report scale. RESULTS: The heritability of depressive symptoms was 16.2 % (95 % CI = 10.7-22.1) prenatally and 25.7 % (95 % CI = 19.2-32.2) postnatally. The correlation between risk factors for prenatal and postnatal depressive symptoms was at unity (r = 1.00) for genetic effects, and at disunity (r = 0.36) for environmental effects. The genetic effects for postnatal depressive symptoms were 1.7 times larger compared to prenatal depressive symptoms. LIMITATIONS: Although genes for depression become more influential postpartum, only future studies can inform on the mechanisms for such a socio-biological augmentation of effect. CONCLUSION: Genetic risk factors for prenatal and postnatal depressive symptoms are indistinguishable in kind, with greater impact after birth, whereas environmental risk factors for depression symptoms are mostly non-overlapping before and after birth. These findings indicate that interventions could be of different kind before and after birth.
Assuntos
Depressão Pós-Parto , Complicações na Gravidez , Gravidez , Feminino , Humanos , Depressão Pós-Parto/epidemiologia , Depressão Pós-Parto/genética , Depressão Pós-Parto/diagnóstico , Estudos de Coortes , Estudos Prospectivos , Depressão/epidemiologia , Depressão/genética , Período Pós-Parto , Vitaminas , Fatores de Risco , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/genéticaRESUMO
Postpartum depression (PPD) is a serious mood disorder that tends to occur after the delivery, which may bring lifelong consequences to women and their families in terms of family relationships, social relationships, and mental health. Currently, various risk factors including environmental factors and genetic factors that may induce postpartum depression have been extensively studied. In this review, we suggest that postpartum women's susceptibility to postpartum depression may be the result of the interaction between the genes associated with postpartum depression as well as the interaction between genetic and environmental factors. We reviewed the genes that have been studied in postpartum depression, including genes related to the synthesis, metabolism, and transport of monoamine neurotransmitters, key molecules of the HPA axis, and the kynurenine pathway. These studies have found more or less gene-gene and gene-environment interactions, so we will discuss these issues in more detail. However, so far, the conclusions of these risk factors, especially genetic factors, are not completely consistent in the occurrence and exacerbation of symptoms in postpartum depression, and it is not clear how these risk factors specifically participate in the pathological mechanism of the disease and play a role. We conclude that the role of genetic polymorphisms, including genetic and epigenetic processes, in the occurrence and development of postpartum depression, is complex and ambiguous. We also note that interactions between multiple candidate genes and the environment have been suggested as causes of depression, suggesting that more definitive research is needed to understand the heritability and susceptibility of PPD. Overall, our work supports the hypothesis that postpartum depression is more likely to be caused by a combination of multiple genetic and environmental factors than by a single genetic or environmental influence.
Assuntos
Depressão Pós-Parto , Feminino , Humanos , Depressão Pós-Parto/genética , Depressão Pós-Parto/epidemiologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Fatores de Risco , Polimorfismo GenéticoRESUMO
OBJECTIVE: To investigate the association of postpartum depressive symptoms (PDS) and self-harm ideation with n-methyl-d-aspartate (NMDA) receptor GRIN2B and GRIN3A gene polymorphisms and other risk factors in women undergoing cesarean section. METHODS: A total of 362 parturients undergoing cesarean section under lumbar anesthesia were selected and their postpartum depression level was assessed by the Edinburgh Postpartum Depression Scale (EPDS) at 42 days postpartum, with an EPDS score of 9/10 as the cut-off value. Three GRIN2B SNP loci (rs1805476, rs3026174, rs4522263) and five GRIN3A SNP loci (rs1983812, rs2050639, rs2050641, rs3739722, rs10989563) were selected for genotype detection. The role of each SNP, linkage disequilibrium and haplotypes in the development of postpartum depression was analyzed. Logistic regression analysis was performed for related risk factors. RESULTS: PDS incidence was 16.85%, and self-harm ideation incidence was 13.54%. Univariate analysis showed that GRIN2B rs1805476, rs3026174 and rs4522263 gene polymorphisms were associated with PDS (p < 0.05), with GRIN2B rs4522263 gene also associated with maternal self-harm ideation. GRIN3A rs1983812, rs2050639, rest rs2050641, rs3739722 and rs10989563 alleles were not associated with PDS. Logistic regression analysis indicated that high pregnancy stress, as well as rs1805476 and rs4522263 alleles were PDS risk factors following cesarean delivery. GRIN2B (TTG p = 0.002) and GRIN3A (TGTTC p = 0.002) haplotypes were associated with the lower PDS incidence and higher PDS incidence respectively. CONCLUSION: GRIN2B rs1805476 GG genotype, rs4522263 CC genotype and high stress during pregnancy were risk factors for PDS, whilst a significantly higher incidence of self-harm ideation was evident in parturients carrying GRIN2B rs4522263 CC genotype.
Assuntos
Cesárea , Depressão Pós-Parto , Receptores de N-Metil-D-Aspartato , Comportamento Autodestrutivo , Feminino , Humanos , Gravidez , Cesárea/efeitos adversos , Cesárea/psicologia , Depressão/epidemiologia , Depressão/etiologia , Depressão/genética , Depressão/psicologia , Depressão Pós-Parto/epidemiologia , Depressão Pós-Parto/etiologia , Depressão Pós-Parto/genética , Depressão Pós-Parto/psicologia , População do Leste Asiático/genética , População do Leste Asiático/psicologia , Genótipo , Haplótipos , Parto/genética , Parto/psicologia , Polimorfismo Genético , Período Pós-Parto , Estudos Prospectivos , Receptores de N-Metil-D-Aspartato/genética , Fatores de Risco , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/etiologia , Comportamento Autodestrutivo/genética , Comportamento Autodestrutivo/psicologia , Estresse Psicológico/epidemiologia , Estresse Psicológico/genéticaRESUMO
Postpartum depression (PPD) is a leading cause of morbidity and mortality among women. Clinically, the administration and withdrawal of supraphysiologic estradiol and progesterone (E2 + P) can cause affective symptom reoccurrence in women with a history of PPD, but not matched controls. To investigate the cellular basis underlying this differential affective response, lymphoblastoid cell lines (LCLs) were derived from women with and without past PPD and compared transcriptomically in hormone conditions mimicking pregnancy and parturition: supraphysiologic E2 + P-addback; supraphysiologic E2 + P-withdrawal; and no added E2 + P (Baseline). RNA-sequencing identified unique differentially expressed genes (DEGs) in all hormone conditions, but the majority tended to be downregulated in PPD and observed in E2 + P-addback. Two of these DEGs were evolutionarily conserved cellular stress regulators: IMPACT, an integrative response protein maintaining translational homeostasis, and WWTR1, a transcriptional coactivator in the 'Hippo' pathway mediating cell proliferation and survival. Correspondingly, significant gene network modules were linked to cell cycle progression, estrogen response, and immune dysregulation, suggesting innate differences in intracellular signaling in PPD. In certain hormone conditions, PPD LCLs displayed increased GATA3 expression (an upstream regulator of IMPACT and WWTR1) and differentially phosphorylated eiF2α (the ultimate downstream target of IMPACT). Taken together, these transcriptomic data primarily implicate innately dysregulated cellular responses as potentially influencing mood and/or escalating PPD risk. Furthermore, the intrinsic downregulation of IMPACT's translation and WWTR1's transcription networks may suggest a novel link between PPD and a compromised ability to maintain homeostasis in the context of cellular stress occurring during pregnancy and parturition.
Assuntos
Depressão Pós-Parto , Gravidez , Feminino , Humanos , Depressão Pós-Parto/genética , Depressão Pós-Parto/metabolismo , Redes Reguladoras de Genes/genética , Estradiol , Progesterona , EstrogêniosRESUMO
PURPOSE: The aim of this study was to conduct an association analysis of depressive symptoms and polymorphisms in the ESR1, PGR, CYP19A1, and COMT genes in pregnant and postpartum women. METHODS: The Franconian Maternal Health Evaluation Study (FRAMES) recruited healthy pregnant women prospectively for assessment of maternal and fetal health. The German version of the 10-item Edinburgh Postnatal Depression Scale (EPDS) was completed at three time points in this prospective cohort study. Visit 1 was at study entry in the third trimester of pregnancy, visit 2 was shortly after birth, and visit 3 was 6-8 months after birth. Germline DNA and depression measurements from 361 pregnant women were available for analysis. Six single nucleotide polymorphisms (SNPs) in the above-mentioned genes were genotyped. After reconstruction of haplotypes for PGR (rs1042838 and rs10895068) and CYP19A1 (rs10046 and rs4646), a multifactorial linear mixed model was applied to the data to describe the association between haplotypes and depression values. The single SNPs for ESR1 (rs488133) and COMT (rs4680) were analyzed separately using linear mixed models analogously. RESULTS: The mean antepartum EPDS measurement was 5.1, the mean postpartal measurement after 48-72 h was 3.5, and the mean value 6-8 months postpartum was 4.2. The SNPs in PGR were reconstructed into three haplotypes. The most common haplotype was GG, with 63.43% of patients carrying two copies and 33.52% carrying one copy. For haplotype GA, the group of carriers of two copies (0.28%) was combined with the carriers of one copy (9.70%). Haplotype reconstruction using CYP19A1 SNPs resulted in three haplotypes. The most common haplotype was TC, with 25.48% of patients carrying two copies and 51.52% one copy. None of the haplotype blocks and neither of the two single SNPs showed any significant associations with EPDS values. CONCLUSIONS: The candidate haplotypes analyzed in PGR and CYP19A1 and single SNPs in ESR1 and COMT did not show any association with depression scores as assessed by EPDS in this cohort of healthy unselected pregnant women.
Assuntos
Depressão Pós-Parto , Depressão , Feminino , Humanos , Gravidez , Depressão/genética , Depressão/diagnóstico , Estudos Prospectivos , Genótipo , Depressão Pós-Parto/genética , Depressão Pós-Parto/diagnóstico , Parto , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Postpartum depression (PPD) is a serious health care issue that affects a substantial share of women giving birth. PPD is considered a severe stress response that is likely associated with impaired HPA-axis activity. However, genetic findings regarding HPA-axis effects on PPD are scarce and inconsistent. Inconsistencies may be due to the neglect of environmental (stressful) events such as perinatal trauma or averse subjective birth experiences associated with PPD. Therefore, the present study aims to investigate whether the NR3C1 gene and subjective birth experience interact on PPD and postpartum bonding to the child. N = 277 mothers provided gene samples and self-report data on PPD and postpartum bonding. We genotyped 11 polymorphisms on the NR3C1 gene (including the prominent BCL1) and conducted haplotype analyses. A negative subjective birth experience was associated with both PPD and maternal postpartum bonding. Our results further show a significant main effect of NR3C1 haplotype (F1, 275 = 6.42, p = .012, η2 =.023) and a haplotype x birth experience interaction (F1, 274 = 4.57, p = .033, η2 =.016) on PPD. We did not find any NR3C1 haplotype effects on bonding. Our results support the assumption that the glucocorticoid receptor coding NR3C1 gene is involved in the development of PPD. These gene effects become particularly important in presence of a negative environmental event such as the subjective birth experience. This finding allows more targeted preventions in terms of being particularly sensitive to potentially harming environmental influences that may present even stronger risk factors for genetically vulnerable women.