A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression

Brain cellular heterogeneity may bias cell type specific DNA methylation patterns, influencing findings in psychiatric epigenetic studies. We performed fluorescence activated cell sorting (FACS) of neuronal nuclei and Illumina HM450 DNA methylation profiling in post mortem frontal cortex of 29 major depression and 29 matched controls. We identify genomic features and ontologies enriched for cell type specific epigenetic variation. Using the top cell epigenotype specific (CETS) marks, we generated a publically available R package, “CETS,” capable of quantifying neuronal proportions and generating in silico neuronal profiles from DNA methylation data. We demonstrate a significant overlap in major depression DNA methylation associations between FACS separated and CETS model generated neuronal profiles relative to bulk profiles. CETS derived neuronal proportions correlated significantly with age in the frontal cortex and cerebellum and accounted for epigenetic variation between brain regions. CETS based control of cellular heterogeneity will enable more robust hypothesis testing in the brain

Predictors of Postpartum Depression: A Comprehensive Review of the Last Decade of Evidence

Postpartum depression (PPD) is one of the most frequent complications of childbirth affecting 500,000 women annually (prevalence 10% to 15%). Despite the documented adverse outcomes for mother and child, there remains a great need to develop prospective approaches to identify women at risk. This review examines some of the best-characterized molecular and clinical risk factors for PPD. We illustrate that this is a growing literature but there remains a lack of reliable molecular predictors for PPD. Current best predictors are clinical assessments for psychiatric history and adverse life events, highlighting the need for increased depression screening across the perinatal period

The longitudinal effects of stress and fear on psychiatric symptoms in mothers during the COVID-19 pandemic

The COVID-19 pandemic has been particularly difficult for mothers. Women with a history of peripartum depression (PPD) may be vulnerable to relapse. We sought to understand changes in depressive and anxious symptoms throughout the pandemic and which stressors increased symptoms in women with a history of PPD. In June 2020, all US participants with a history of PPD (n = 12,007) in the global MomGenes Fight PPD study were invited to the COVID-19 follow-up study. Respondents (n = 2163, 18%) were sent biweekly and then monthly surveys until January 31, 2022. We employed time-varying effects models to evaluate trajectories of depressive (patient health questionnaire, PHQ-9) and anxious (generalized anxiety disorder, GAD-7) symptoms and to estimate longitudinal associations between perceived stress, fears, COVID-19 case rates, and symptoms. Peaks of PHQ-9, GAD-7, PSS, and perceived COVID-19 risk scores corresponded with timing of national COVID-19 case surges. High perceived stress was the strongest predictor of PHQ-9 (beta = 7.27; P = 1.48e − 38) and GAD-7 (beta = 7.73; P = 6.19e − 70). Feeling lack of control and unlikely to survive increased PHQ-9 and GAD-7 scores by 2 points. COVID-19 case rates, pandemic restrictions, and region were not independently associated with symptoms. This study suggests that the collective trauma of the pandemic has significantly affected mothers with a history of PPD, exemplified by high levels of perceived stress and the strong association with depressive and anxious symptoms. The next pandemic phase is uncertain, but will continue to influence mental health collectively and dynamically. Interventions must be flexible and responsive and should address fear, trauma, and feelings of control, particularly for mothers with a history of PPD

Bidirectional Psychoneuroimmune Interactions in the Early Postpartum Period Influence Risk of Postpartum Depression

More than 500,000 U.S. women develop postpartum depression (PPD) annually. Although psychosocial risks are known, the underlying biology remains unclear. Dysregulation of the immune inflammatory response and the hypothalamic–pituitary–adrenal (HPA) axis are associated with depression in other populations. While significant research on the contribution of these systems to the development of PPD has been conducted, results have been inconclusive. This is partly because few studies have focused on whether disruption in the bidirectional and dynamic interaction between the inflammatory response and the HPA axis together influence PPD. In this study, we tested the hypothesis that disruption in the inflammatory-HPA axis bidirectional relationship would increase the risk of PPD. Plasma pro- and anti-inflammatory cytokines were measured in women during the 3rd trimester of pregnancy and on Days 7 and 14, and Months 1, 2, 3, and 6 after childbirth. Saliva was collected 5 times the day preceding blood draws for determination of cortisol area under the curve (AUC) and depressive symptoms were measured using the Edinburgh Postpartum Depression Survey (EPDS). Of the 152 women who completed the EPDS, 18% were depressed according to EDPS criteria within the 6 months postpartum. Cortisol AUC was higher in symptomatic women on Day 14 (p = .017). To consider the combined effects of cytokines and cortisol on predicting symptoms of PPD, a multiple logistic regression model was developed that included predictors identified in bivariate analyses to have an effect on depressive symptoms. Results indicated that family history of depression, day 14 cortisol AUC, and the day 14 IL8/IL10 ratio were significant predictors of PPD symptoms. One unit increase each in the IL8/IL10 ratio and cortisol AUC resulted in 1.50 (p = 0.06) and 2.16 (p = 0.02) fold increases respectively in the development of PPD. Overall, this model correctly classified 84.2% of individuals in their respective groups. Findings suggest that variability in the complex interaction between the inflammatory response and the HPA axis influence the risk of PPD

Adverse life events increase risk for postpartum psychiatric episodes: a population based epidemiologic study

Background: Trauma histories may increase risk of perinatal psychiatric episodes and other comorbidity. We designed an epidemiological population-based cohort study to explore if adverse childhood experiences (ACE) in girls increases risk of later postpartum psychiatric episodes. Methods: Using Danish registers, we identified women born in Denmark between January 1980 and December 1998, (129,439 childbirths). Exposure variables were ACE between age 0-15 including: (1) family disruption, (2) parental somatic illness, (3) parental labor market exclusion, (4) parental criminality, (5) parental death, (6) placement in out-of-home care, and (7).parental psychopathology excluding substance use disorders and (8) parental substance use disorder. The primary outcome was first occurrence of in- or outpatient contact 0-6 months (0-182 days) postpartum at a psychiatric treatment facility with any psychiatric diagnoses, ICD-10, F00-F99 (N=651). We conducted survival analyses using Cox proportional hazard regressions of postpartum psychiatric episodes. Results: Approximately 52% of the sample experienced ACE that significantly increased risk of any postpartum psychiatric diagnosis. Highest risks were observed among women who experienced out of home placement, hazard ratio (HR) 2.57 (95% CI: 1.90-3.48). Women experiencing 2 adverse life events had higher risks of postpartum psychiatric diagnosis HR: 1.88 (95% CI: 1.51-2.36), compared to those with 1 ACE, HR: 1.24 (95% CI: 1.03-49) and no ACE, HR: 1.00 (reference group). Conclusions: ACE primarily due to parental psychopathology and disability contributes to increased risk of postpartum psychiatric episodes; and greater numbers of ACE increases risk for postpartum psychiatric illness with an observed dose-response effect. Future work should explore genetic and environmental factors that increase risk and/or confer resilience

Recommendations to encourage participation of individuals from diverse backgrounds in psychiatric genetic studies

We present innovative research practices in psychiatric genetic studies to ensure representation of individuals from diverse ancestry, sex assigned at birth, gender identity, age, body shape and size, and socioeconomic backgrounds. Due to histories of inappropriate and harmful practices against marginalized groups in both psychiatry and genetics, people of certain identities may be hesitant to participate in research studies. Yet their participation is essential to ensure diverse representation, as it is incorrect to assume that the same genetic and environmental factors influence the risk for various psychiatric disorders across all demographic groups. We present approaches developed as part of the Eating Disorders Genetics Initiative (EDGI), a study that required tailored approaches to recruit diverse populations across many countries. Considerations include research priorities and design, recruitment and study branding, transparency, and community investment and ownership. Ensuring representation in participants is costly and funders need to provide adequate support to achieve diversity in recruitment in prime awards, not just as supplemental afterthoughts. The need for diverse samples in genetic studies is critical to minimize the risk of perpetuating health disparities in psychiatry and other health research. Although the EDGI strategies were designed specifically to attract and enroll individuals with eating disorders, our approach is broadly applicable across psychiatry and other fields

Longitudinal study of DNA methylation during the first 5 years of life.

Background: Early life epigenetic programming influences adult health outcomes. Moreover, DNA methylation levels have been found to change more rapidly during the first years of life. Our aim was the identification and characterization of the CpG sites that are modified with time during the first years of life. We hypothesize that these DNA methylation changes would lead to the detection of genes that might be epigenetically modulated by environmental factors during early childhood and which, if disturbed, might contribute to susceptibility to diseases later in life. Methods: The study of the DNA methylation pattern of 485577 CpG sites was performed on 30 blood samples from 15 subjects, collected both at birth and at 5 years old, using Illumina® Infinium 450 k array. To identify differentially methylated CpG (dmCpG) sites, the methylation status of each probe was examined using linear models and the Empirical Bayes Moderated t test implemented in the limma package of R/Bioconductor. Surogate variable analysis was used to account for batch effects. Results: DNA methylation levels significantly changed from birth to 5 years of age in 6641 CpG sites. Of these, 36.79 % were hypermethylated and were associated with genes related mainly to developmental ontology terms, while 63.21 % were hypomethylated probes and associated with genes related to immune function. Conclusions: Our results suggest that DNA methylation alterations with age during the first years of life might play a significant role in development and the regulation of leukocyte-specific functions. This supports the idea that blood leukocytes experience genome remodeling related to their interaction with environmental factors, underlining the importance of environmental exposures during the first years of life and suggesting that new strategies should be take into consideration for disease prevention

Postpartum psychiatric disorders

Pregnancy is a complex and vulnerable period that presents a number of challenges to women, including the development of postpartum psychiatric disorders (PPDs). These disorders can include postpartum depression and anxiety, which are relatively common, and the rare but more severe postpartum psychosis. In addition, other PPDs can include obsessive–compulsive disorder, post-traumatic stress disorder and eating disorders. The aetiology of PPDs is a complex interaction of psychological, social and biological factors, in addition to genetic and environmental factors. The goals of treating postpartum mental illness are reducing maternal symptoms and supporting maternal–child and family functioning. Women and their families should receive psychoeducation about the illness, including evidence-based discussions about the risks and benefits of each treatment option. Developing effective strategies in global settings that allow the delivery of targeted therapies to women with different clinical phenotypes and severities of PPDs is essential