Comprehensive Sex-Stratified Genetic Analysis of 28 Blood Biomarkers and Depression Reveals a Significant Association between Depression and Low Levels of Total Protein in Females.

Introduction: Major depression (MD) is more common amongst women than men, and MD episodes have been associated with fluctuations in reproductive hormones amongst women. To investigate biological underpinnings of heterogeneity in MD, the associations between depression, stratified by sex and including perinatal depression (PND), and blood biomarkers, using UK Biobank (UKB) data, were evaluated, and extended to include the association of depression with biomarker polygenic scores (PGS), generated as proxy for each biomarker. Method: Using female (N = 39,761) and male (N = 38,821) UKB participants, lifetime MD and PND were tested for association with 28 blood biomarkers. A GWAS was conducted for each biomarker and genetic correlations with depression subgroups were estimated. Using independent data from the Australian Genetics of Depression Study, PGS were constructed for each biomarker, and tested for association with depression status (n [female cases/controls] = 9,006/6,442; n [male cases/controls] = 3,106/6,222). Regions of significant local genetic correlation between depression subgroups and biomarkers highlighted by the PGS analysis were identified. Results: Depression in females was significantly associated with levels of twelve biomarkers, including total protein (OR = 0.90, CI = [0.86, 0.94], p = 3.9 × 10-6) and vitamin D (OR = 0.94, CI = [0.90, 0.97], p = 2.6 × 10-4), and PND with five biomarker levels, also including total protein (OR = 0.88, CI = [0.81, 0.96], p = 4.7 × 10-3). Depression in males was significantly associated with levels of eleven biomarkers. In the independent Australian Genetics of Depression Study, PGS analysis found significant associations for female depression and PND with total protein (female depression: OR = 0.93, CI = [0.88, 0.98], p = 3.6 × 10-3; PND: OR = 0.91, CI = [0.86, 0.96], p = 1.1 × 10-3), as well as with vitamin D (female depression: OR = 0.93, CI = [0.89, 0.97], p = 2.0 × 10-3; PND: OR = 0.92, CI = [0.87, 0.97], p = 1.4 × 10-3). The male depression sample did not report any significant results, and the point estimate of total protein (OR = 0.98, CI = [0.92-1.04], p = 4.7 × 10-1) did not indicate any association. Local genetic correlation analysis highlighted significant genetic correlation between PND and total protein, located in 5q13.3 (rG = 0.68, CI = [0.33, 1.0], p = 3.6 × 10-4). Discussion and Conclusion: Multiple lines of evidence from genetic analysis highlight an association between total serum protein levels and depression in females. Further research involving prospective measurement of total protein and depressive symptoms is warranted.

Meta-analysis of epigenetic aging in schizophrenia reveals multifaceted relationships with age, sex, illness duration, and polygenic risk.

BACKGROUND: The study of biological age acceleration may help identify at-risk individuals and reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging in schizophrenia (SCZ), a mental illness that is associated with an increased prevalence of age-related disabilities and morbidities. In a whole blood DNAm sample of 1090 SCZ cases and 1206 controls across four European cohorts, we performed a meta-analysis of differential aging using three DNAm clocks (i.e., Hannum, Horvath, and Levine). To dissect how DNAm aging contributes to SCZ, we integrated information on duration of illness and SCZ polygenic risk, as well as stratified our analyses by chronological age and biological sex. RESULTS: We found that blood-based DNAm aging is significantly altered in SCZ independent from duration of the illness since onset. We observed sex-specific and nonlinear age effects that differed between clocks and point to possible distinct age windows of altered aging in SCZ. Most notably, intrinsic cellular age (Horvath clock) is decelerated in SCZ cases in young adulthood, while phenotypic age (Levine clock) is accelerated in later adulthood compared to controls. Accelerated phenotypic aging was most pronounced in women with SCZ carrying a high polygenic burden with an age acceleration of + 3.82 years (CI 2.02-5.61, P = 1.1E-03). Phenotypic aging and SCZ polygenic risk contributed additively to the illness and together explained up to 14.38% of the variance in disease status. CONCLUSIONS: Our study contributes to the growing body of evidence of altered DNAm aging in SCZ and points to intrinsic age deceleration in younger adulthood and phenotypic age acceleration in later adulthood in SCZ. Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings indicate that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. Our study did not find that DNAm aging could be explained by the duration of illness of patients, but we did observe age- and sex-specific effects that warrant further investigation. Finally, our results show that combining genetic and epigenetic predictors can improve predictions of disease outcomes and may help with disease management in schizophrenia.

ARFID Genes and Environment (ARFID-GEN): study protocol.

BACKGROUND: The Avoidant Restrictive Food Intake Disorder - Genes and Environment (ARFID-GEN) study is a study of genetic and environmental factors that contribute to risk for developing ARFID in children and adults. METHODS: A total of 3,000 children and adults with ARFID from the United States will be included. Parents/guardians and their children with ARFID (ages 7 to 17) and adults with ARFID (ages 18 +) will complete comprehensive online consent, parent verification of child assent (when applicable), and phenotyping. Enrolled participants with ARFID will submit a saliva sample for genotyping. A genome-wide association study of ARFID will be conducted. DISCUSSION: ARFID-GEN, a large-scale genetic study of ARFID, is designed to rapidly advance the study of the genetics of eating disorders. We will explicate the genetic architecture of ARFID relative to other eating disorders and to other psychiatric, neurodevelopmental, and metabolic disorders and traits. Our goal is for ARFID to deliver "actionable" findings that can be transformed into clinically meaningful insights. TRIAL REGISTRATION: ARFID-GEN is a registered clinical trial: clinicaltrials.gov NCT05605067.

Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression.

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).

The Mood, Mother and Child Study: Protocol for a Prospective Longitudinal Study and Randomized Controlled Trial.

BACKGROUND: Perinatal depression affects >400,000 mother-child dyads in the United States every year and is associated with numerous adverse maternal and child developmental outcomes. Previous research implicates the dysregulation of oxytocin and the hypothalamic-pituitary-adrenal (HPA) axis functioning in mothers and children as potential mechanisms mediating or moderating the transmission of risk associated with maternal depression. OBJECTIVE: The Mood, Mother and Child study will examine the psychobiological sources of risk and resilience within mother-child dyads affected by maternal depression. This manuscript describes (1) the study rationale and aims, (2) the research design and procedures and how they were altered in response to the COVID-19 pandemic, and (3) the data analysis plan to test the study hypotheses. METHODS: This is a prospective longitudinal study with an embedded randomized controlled trial that examines (1) correlations among postpartum depression and anxiety symptoms, maternal and child oxytocin and HPA axis functioning, and child developmental outcomes and (2) the causal relationship between exogenous oxytocin and HPA reactivity. This study is funded by the National Institute of Child Health and Human Development with institutional review board approval. RESULTS: Recruitment and data collection have commenced, and the expected results will be available in 2024. Analyses are presented for testing the proposed hypotheses. CONCLUSIONS: The unique combination of a prospective longitudinal research design with an embedded randomized controlled trial will allow the Mood, Mother and Child study to apply a developmental lens to the study of maternal depression and anxiety symptoms from birth to middle childhood and the psychobiological mechanisms promoting risk and resiliency for both mother and child outcomes. This will be the first study that simultaneously evaluates (1) the role of oxytocin using multiple methodologies, (2) the causal relationships between exogenous oxytocin and HPA axis functioning among mothers with differing levels of depression and anxiety symptoms, and (3) the multiple mediating and moderating roles of parenting behaviors and maternal and child psychobiological characteristics. The goals of these aims are to provide insights into the psychobiological effects of oxytocin in women and inform future clinical trials to treat perinatal mood disorders. TRIAL REGISTRATION: ClinicalTrials.gov NCT03593473; https://classic.clinicaltrials.gov/ct2/show/NCT03593473. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51132.

Arfid Genes and Environment (ARFID-GEN): Study Protocol.

Background: The Avoidant Restrictive Food Intake Disorder Genes and Environment (ARFID-GEN) study is a study of genetic and environmental factors that contribute to risk for developing ARFID in children and adults. Methods: A total of 3,000 children and adults with ARFID from the United States will be included. Parents/guardians and their children with ARFID (ages 7 to 17) and adults with ARFID (ages 18+) will complete comprehensive online consent, parent verification of child assent (when applicable), and phenotyping. Enrolled participants with ARFID will submit a saliva sample for genotyping. A genome-wide association study of ARFID will be conducted. Discussion: ARFID-GEN, a large-scale genetic study of ARFID, is designed to rapidly advance the study of the genetics of eating disorders. We will explicate the genetic architecture of ARFID relative to other eating disorders and to other psychiatric, neurodevelopmental, and metabolic disorders and traits. Our goal is for ARFID to deliver "actionable" findings that can be transformed into clinically meaningful insights. Trial registration: ARFID-GEN is a registered clinical trial: clinicaltrials.gov NCT05605067.

A method to improve the reproducibility of findings from epigenome- and transcriptome-wide association studies.

Reproducibility is a cornerstone of scientific progress. In epigenome- and transcriptome-wide association studies (E/TWAS) failure to reproduce may be the result of false discoveries. Whereas multiple methods exist to control false discoveries due to sampling error, minimizing false discoveries due to outliers and other data artefacts remains challenging. We propose a robust E/TWAS approach that outperforms alternative methods to improve reproducibility such as split-half replication. Furthermore, robust E/TWAS results in only a minor loss of power if there are no outliers and can in the presence of outliers, likely a more realistic scenario, even be more powerful than regular E/TWAS.

The PPD-ACT app in Canada: feasibility and a latent class analysis of participants with postpartum depression recruited to a psychiatric genetics study using a mobile application.

BACKGROUND: Postpartum depression (PPD) and postpartum psychosis (PPP) are linked to negative consequences for women and families. Virtual applications present a solution to the challenge of recruiting large samples for genetic PPD/PPP research. This study aimed to evaluate the feasibility of a protocol for enrolling Canadian women with PPD and PPP to a large international psychiatric genetics study using a mobile application (PPD-ACT), and identify clinically distinct subtypes of PPD in the recruited sample. METHODS: From April 2017-June 2019, Canadian women provided phenotypic data through the PPD-ACT app. Requests for a genetic sample were made from those with a current or past PPD episode based on an Edinburgh Postnatal Depression Scale (EPDS) score > 12 with onset in pregnancy or 0-3 months postpartum, and from those self-reporting lifetime PPP. Latent class analysis (LCA) was used to identify clinically distinct PPD subgroups based on participant responses to the EPDS scale. RESULTS: We identified 797 PPD cases, 404 of whom submitted DNA. There were 109 PPP cases, with 66 submitting DNA. PPD cases (86.7% White, mean 4.7 +/- 7.0 years since their episode) came from across Canadian provinces/territories. LCA identified two PPD classes clinically distinct by symptom severity: [1] moderate-severity (mean EPDS = 18.5+/- 2.5; 8.6% with suicidality), and [2] severe (mean EPDS = 24.5+/- 2.1; 52.8% with suicidality). CONCLUSIONS: A mobile application rapidly collected data from individuals with moderate and severe symptoms of PPD, an advantage for genetics where specificity is optimal, as well as from women with a history of PPP, supporting future work using this approach.

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.

Lifetime prevalence and correlates of perinatal depression in a case-cohort study of depression.

OBJECTIVES: This study sought to evaluate the prevalence, timing of onset and duration of symptoms of depression in the perinatal period (PND) in women with depression, according to whether they had a history of depression prior to their first perinatal period. We further sought to identify biopsychosocial correlates of perinatal symptoms in women with depression. DESIGN AND SETTING: The Australian Genetics of Depression Study is an online case cohort study of the aetiology of depression. For a range of variables, women with depression who report significant perinatal depressive symptoms were compared with women with lifetime depression who did not experience perinatal symptoms. PARTICIPANTS: In a large sample of parous women with major depressive disorder (n=7182), we identified two subgroups of PND cases with and without prior depression history (n=2261; n=878, respectively). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was a positive screen for PND on the lifetime version of the Edinburgh Postnatal Depression Scale. Descriptive measures reported lifetime prevalence, timing of onset and duration of PND symptoms. There were no secondary outcome measures. RESULTS: The prevalence of PND among parous women was 70%. The majority of women reported at least one perinatal episode with symptoms both antenatally and postnatally. Of women who experienced depression prior to first pregnancy, PND cases were significantly more likely to report more episodes of depression (OR=1.15 per additional depression episode, 95% CI 1.13 to 1.17, p<0.001), non-European ancestry (OR 1.5, 95% CI 1.0 to 2.1, p=0.03), severe nausea during pregnancy (OR 1.3, 95% CI 1.1 to 1.6, p=0.006) and emotional abuse (OR 1.4, 95% CI 1.1 to 1.7, p=0.005). CONCLUSIONS: The majority of parous women with lifetime depression in this study experienced PND, associated with more complex, severe depression. Results highlight the importance of perinatal assessments of depressive symptoms, particularly for women with a history of depression or childhood adverse experiences.

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.

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

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.

App-Based Ecological Momentary Assessment to Enhance Clinical Care for Postpartum Depression: Pilot Acceptability Study.

BACKGROUND: Wearable tracking devices and mobile health technology are increasingly used in an effort to enhance clinical care and the delivery of personalized medical treatment. Postpartum depression is the most frequently diagnosed complication of childbirth; however, significant gaps in screening and treatment remain. OBJECTIVE: This study aims to investigate the clinical utility, predictive ability, and acceptability of using ecological momentary assessment to collect daily mood, sleep, and activity data through the use of an Apple Watch and mobile app among women with postpartum depression. METHODS: This was a pilot study consisting of 3 in-person research visits over the course of a 6-week enrollment period. Questionnaires to assess depression, anxiety, and maternal functioning were periodically collected, along with daily self-reported symptoms and passively collected physiological data via an Apple Watch. Feedback was collected from study participants and the study clinician to determine the utility and acceptability of daily tracking. Logistic regression was used to determine whether mood scores in the 2 weeks before a visit predicted scores at follow-up. Compliance with daily assessments was also measured. RESULTS: Of the 26 women enrolled, 23 (88%) completed the 6-week study period. On average, the participants completed 67% (34.4/51.5 days) of all active daily assessments and 74% (38/51.5 days) of all passive measures. Furthermore, all 23 participants completed the 3 required visits with the research team. Predictive correlations were found between self-reported mood and Edinburgh Postnatal Depression Scale score at follow-up, self-reported anxiety and EDPS, and sleep quality and Edinburgh Postnatal Depression Scale. CONCLUSIONS: Using ecological momentary assessment to track daily symptoms of postpartum depression using a wearable device was largely endorsed as acceptable and clinically useful by participants and the study clinician and could be an innovative solution to increase care access during the COVID-19 pandemic.

Perinatal depression is associated with a higher polygenic risk for major depressive disorder than non-perinatal depression.

BACKGROUND: Distinctions between major depressive disorder (MDD) and perinatal depression (PND) reflect varying views of PND, from a unique etiological subtype of MDD to an MDD episode that happens to coincide with childbirth. This case-control study investigated genetic differences between PND and MDD outside the perinatal period (non-perinatal depression or NPD). METHODS: We conducted a genome-wide association study using PND cases (Edinburgh Postnatal Depression Scale score ≥ 13) from the Australian Genetics of Depression Study 2018 data (n = 3804) and screened controls (n = 6134). Results of gene-set enrichment analysis were compared with those of women with non-PND. For six psychiatric disorders/traits, genetic correlations with PND were evaluated, and logistic regression analysis reported polygenic score (PGS) association with both PND and NPD. RESULTS: Genes differentially expressed in ovarian tissue were significantly enriched (stdBeta = 0.07, p = 3.3e-04), but were not found to be associated with NPD. The genetic correlation between PND and MDD was 0.93 (SE = 0.07; p = 3.5e-38). Compared with controls, PGS for MDD are higher for PND cases (odds ratio [OR] = 1.8, confidence interval [CI] = [1.7-1.8], p = 9.5e-140) than for NPD cases (OR = 1.6, CI = [1.5-1.7], p = 1.2e-49). Highest risk is for those reporting both antenatal and postnatal depression, irrespective of prior MDD history. CONCLUSIONS: PND has a high genetic overlap with MDD, but points of distinction focus on differential expression in ovarian tissue and higher MDD PGS, particularly for women experiencing both antenatal and postpartum PND.

DNA methylation of the KLK8 gene in depression symptomatology.

BACKGROUND: Depression is a common, complex, and debilitating mental disorder estimated to be under-diagnosed and insufficiently treated in society. Liability to depression is influenced by both genetic and environmental risk factors, which are both capable of impacting DNA methylation (DNAm). Accordingly, numerous studies have researched for DNAm signatures of this disorder. Recently, an epigenome-wide association study of monozygotic twins identified an association between DNAm status in the KLK8 (neuropsin) promoter region and severity of depression symptomatology. METHODS: In this study, we aimed to investigate: (i) if blood DNAm levels, quantified by pyrosequencing, at two CpG sites in the KLK8 promoter are associated with depression symptomatology and depression diagnosis in an independent clinical cohort and (ii) if KLK8 DNAm levels are associated with depression, postpartum depression, and depression symptomatology in four independent methylomic cohorts, with blood and brain DNAm quantified by either MBD-seq or 450 k methylation array. RESULTS: DNAm levels in KLK8 were not significantly different between depression cases and controls, and were not significantly associated with any of the depression symptomatology scores after correction for multiple testing (minimum p value for KLK8 CpG1 = 0.12 for 'Depressed mood,' and for CpG2 = 0.03 for 'Loss of self-confidence with other people'). However, investigation of the link between KLK8 promoter DNAm levels and depression-related phenotypes collected from four methylomic cohorts identified significant association (p value < 0.05) between severity of depression symptomatology and blood DNAm levels at seven CpG sites. CONCLUSIONS: Our findings suggest that variance in blood DNAm levels in KLK8 promoter region is associated with severity of depression symptoms, but not depression diagnosis.

The Eating Disorders Genetics Initiative (EDGI): study protocol.

BACKGROUND: The Eating Disorders Genetics Initiative (EDGI) is an international investigation exploring the role of genes and environment in anorexia nervosa, bulimia nervosa, and binge-eating disorder. METHODS: A total of 14,500 individuals with eating disorders and 1500 controls will be included from the United States (US), Australia (AU), New Zealand (NZ), and Denmark (DK). In the US, AU, and NZ, participants will complete comprehensive online phenotyping and will submit a saliva sample for genotyping. In DK, individuals with eating disorders will be identified by the National Patient Register, and genotyping will occur using bloodspots archived from birth. A genome-wide association study will be conducted within EDGI and via meta-analysis with other data from the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED). DISCUSSION: EDGI represents the largest genetic study of eating disorders ever to be conducted and is designed to rapidly advance the study of the genetics of the three major eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorder). We will explicate the genetic architecture of eating disorders relative to each other and to other psychiatric and metabolic disorders and traits. Our goal is for EDGI to deliver "actionable" findings that can be transformed into clinically meaningful insights. TRIAL REGISTRATION: EDGI is a registered clinical trial: clinicaltrials.gov NCT04378101 .

Psychiatric genomics research during the COVID-19 pandemic: A survey of Psychiatric Genomics Consortium researchers.

Between April 20, 2020 and June 19, 2020 we conducted a survey of the membership of the Psychiatric Genomics Consortium (PGC) to explore the impact of COVID-19 on their research and academic careers. A total of 123 individuals responded representing academic ranks from trainee to full professor, tenured and fixed-term appointments, and all genders. The survey included both quantitative and free text responses. Results revealed considerable concern about the impact of COVID-19 on research with the greatest concern reported by individuals in nonpermanent positions and female researchers. Concerns about the availability of funding and the impact of the pandemic on career progression were commonly reported by early career researchers. Recommendations for institutions, organizations such as the PGC, as well as individual senior investigators have been provided to ensure that the futures of early career investigators, especially those underrepresented in academic medicine such as women and underrepresented minorities, are not disproportionately disadvantaged by the COVID-19 pandemic.

HPA axis regulation and epigenetic programming of immune-related genes in chronically stressed and non-stressed mid-life women.

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been associated with altered immune function, but the underlying molecular mechanisms are unclear. Epigenetic processes, including DNA methylation, respond to the glucocorticoid end-products of the HPA axis (cortisol in humans) and could be involved in this neuroendocrine-immune crosstalk. Here we examined the extent to which variations in HPA axis regulation are associated with peripheral blood DNA (CpG) methylation changes in 57 chronically stressed caregivers and 67 control women. DNA methylation was determined with the Illumina 450k array for a panel of genes involved in HPA axis and immune function. HPA axis feedback was assessed with the low-dose dexamethasone suppression test (DST), measuring the extent to which cortisol secretion is suppressed by the synthetic glucocorticoid dexamethasone. After multiple testing correction in the entire cohort, higher post-DST cortisol, reflecting blunted HPA axis negative feedback, but not baseline waking cortisol, was associated with lower DNA methylation at eight TNF and two FKBP5 CpG sites. Caregiver group status was associated with lower methylation at two IL6 CpG sites. Since associations were most robust with TNF methylation (32% of the 450k-covered sites), we further examined functionality of this epigenetic signature in cultured peripheral blood mononuclear cells in 33 participants; intriguingly, lower TNF methylation resulted in higher ex vivo TNF mRNA following immune stimulation. Taken together, our findings link chronic stress and HPA axis regulation with epigenetic signatures at immune-related genes, thereby providing novel insights into how aberrant HPA axis function may contribute to heightened inflammation and disease risk.

Psychiatric Genomics Research During the COVID-19 Pandemic: A Survey of Psychiatric Genomics Consortium Researchers.

Between April 20, 2020 and June 19, 2020 we conducted a survey of the membership of the Psychiatric Genomics Consortium (PGC) to explore the impact of COVID-19 on their research and academic careers. A total of 123 individuals responded representing academic ranks from trainee to full professor, tenured and fixed-term appointments, and all genders. The survey included both quantitative and free text responses. Results revealed considerable concern about the impact of COVID-19 on research with the greatest concern reported by individuals in non-permanent positions and female researchers. Concerns about the availability of funding and the impact of the pandemic on career progression were commonly reported by early career researchers. We provide recommendations for institutions, organizations such as the PGC, as well as individual senior investigators to ensure that the futures of early career investigators, especially those underrepresented in academic medicine such as women and underrepresented minorities, are not disproportionately disadvantaged by the COVID-19 pandemic.

Test-statistic inflation in methylome-wide association studies.

Recent years have seen a surge of methylome-wide association studies (MWAS). We observed that many of these studies suffer from test statistic inflation that is most likely caused by commonly used quality control (QC) pipelines not going far enough to remove technical artefacts. To support this claim, we reanalysed GEO datasets with an improved QC pipeline that reduced test-statistic inflation parameter lambda from the original mean/median of 20.16/15.17 to 3.07/1.14. Furthermore, the mean/median number of methylome-wide significant findings was reduced by 65,688/57,805 loci after more thorough QC. To avoid such false positives we argue for more extensive QC and that reporting the test-statistic inflation parameter lambda become standard for all MWAS allowing readers to better assess the risk of false discoveries.