Methylation age acceleration does not predict mortality in schizophrenia

Schizophrenia (SCZ) is associated with high mortality. DNA methylation levels vary over the life course, and pre-selected combinations of methylation array probes can be used to estimate "methylation age" (mAge). mAge correlates highly with chronological age but when it differs, termed mAge acceleration, it has been previously associated with all-cause mortality. We tested the association between mAge acceleration and mortality in SCZ and controls. We selected 190 SCZ cases and 190 controls from the Sweden Schizophrenia Study. Cases were identified from the Swedish Hospital Discharge Register with ≥5 specialist treatment contacts and ≥5 antipsychotic prescriptions. Controls had no psychotic disorder or antipsychotics. Subjects were selected if they had died or survived during follow-up (2:1 oversampling). Extracted DNA was assayed on the Illumina MethylationEPIC array. mAge was regressed on age at sampling to obtain mAge acceleration. Using Cox proportional hazards regression, the association between mAge acceleration and mortality was tested. After quality control, the following were available: n = 126 SCZ died, 63 SCZ alive, 127 controls died, 62 controls alive. In the primary analyses, we did not find a significant association between mAge acceleration and SCZ mortality (adjusted p > 0.005). Sensitivity analyses excluding SCZ cases with pre-existing cancer demonstrated a significant association between the Hannum mAge acceleration and mortality (hazard ratio = 1.13, 95% confidence interval = 1.04-1.22, p = 0.005). Per our pre-specified criteria, we did not confirm our primary hypothesis that mAge acceleration would predict subsequent mortality in people with SCZ, but we cannot rule out smaller effects or effects in patient subsets.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This work was supported by the Swedish Research Council (Vetenskapsrådet, award D0886501 to PFS) and the UK Medical Research Council (award MR/K013807/1 to JM). The Sweden Schizophrenia Study was supported by NIMH R01 MH077139.published version, accepted version, submitted versio

Methylation age acceleration does not predict mortality in schizophrenia.

Schizophrenia (SCZ) is associated with high mortality. DNA methylation levels vary over the life course, and pre-selected combinations of methylation array probes can be used to estimate "methylation age" (mAge). mAge correlates highly with chronological age but when it differs, termed mAge acceleration, it has been previously associated with all-cause mortality. We tested the association between mAge acceleration and mortality in SCZ and controls. We selected 190 SCZ cases and 190 controls from the Sweden Schizophrenia Study. Cases were identified from the Swedish Hospital Discharge Register with ≥5 specialist treatment contacts and ≥5 antipsychotic prescriptions. Controls had no psychotic disorder or antipsychotics. Subjects were selected if they had died or survived during follow-up (2:1 oversampling). Extracted DNA was assayed on the Illumina MethylationEPIC array. mAge was regressed on age at sampling to obtain mAge acceleration. Using Cox proportional hazards regression, the association between mAge acceleration and mortality was tested. After quality control, the following were available: n = 126 SCZ died, 63 SCZ alive, 127 controls died, 62 controls alive. In the primary analyses, we did not find a significant association between mAge acceleration and SCZ mortality (adjusted p > 0.005). Sensitivity analyses excluding SCZ cases with pre-existing cancer demonstrated a significant association between the Hannum mAge acceleration and mortality (hazard ratio = 1.13, 95% confidence interval = 1.04-1.22, p = 0.005). Per our pre-specified criteria, we did not confirm our primary hypothesis that mAge acceleration would predict subsequent mortality in people with SCZ, but we cannot rule out smaller effects or effects in patient subsets

Barriers, Facilitators, and Suggestive HIV Interventions for Women: Preliminary Data from a Secondary Analysis

poster abstractThe Centers for Disease Control and Prevention report that women account for almost ten thousand of those newly diagnosed with HIV annually. Within this group, Latina, non-Latina white and non-Latina black women are particularly affected. The purpose of this secondary analysis was to analyze existing de-identified data for barriers and facilitators for HIV testing and willingness to participate in a vaccine if available. The data were 30 de-identified transcripts of one hour interviews obtained from three groups of women (10 Latinas, 10 non-Latina white, and 10 non- Latina black) during the initial phase of a parent study, “HIV Testing and Women’s Attitudes on HIV Vaccine Trials”: G. Zimet, PI. A semi-structured interview guide had been used to guide the interviews. This sub analysis was conducted with removal of ethnic classification to reduce bias during qualitative review. Three predominant categories of fear, time, and cost emerged from all interviews regardless of ethnicity. Less prominent categories of gender, education, trust, motherhood, discrimination, loss of integrity, invincibility, safety, age, testing accuracy, confidentiality, indifference, pride, lifestyle, divine justice, and stress varied among the three groups. These categories will provide the basis for further analysis to determine subthemes and themes, and if there are themes unique to any of the three groups

Barriers and facilitators to salivary rapid HIV testing in African Americans

OBJECTIVE: To identify barriers and facilitators of voluntary Salivary Rapid HIV testing decisions (SRT) among African Americans in order to develop interventions to improve HIV testing rates and care entry if HIV positive. METHODS: This first phase of a two-phase study used a Comprehensive Health Seeking and Coping Paradigm-based semi-structured interview guide (SSIG) to conduct 10 focus groups of 2-5 African Americans recruited from a large STI Clinic. Content analysis of the focus group transcripts was done using line-by-line analysis, and reviewing sentences and phrases for patterns or core meanings. Patterns were refined and synthesized into descriptive statements. An iterative process of comparison was used to further analyze the data, moving between individual elements of the text specific to participant responses. Meanings that were implicit rather than explicit in the text; and of one whole account with another were used to identify overall patterns of meaning. RESULTS: Of the 38 African American adults recruited, 16 were female with ages 18-49 (M =23) and 22 were male with ages 18-49 (M=29.5). All self identified as heterosexual with most reporting low income and no health insurance. Within the context of barriers and facilitators to SRT, eight themes emerged: Familiarity, Stigma, Fear, Access, Immediacy, Ease, Degree of Responsibility, and Trust. Each theme was not seen exclusively as a barrier or facilitator but was interpreted to be one or the other depending on the aspect of HIV testing being discussed. A gender sub analysis revealed themes of health maintenance and illness management for females and males respectively. CONCLUSIONS: Since there has not been an increase in HIV testing rates in AA’s even with newer SRT technology. The findings support the need to assess barriers and facilitators to testing decisions in order to increase testing rates. The themes also suggest the need for tailored community based interventions that decrease fear, stigma and increase trust in testing methods and providers for HIV and STI screening

Genome-wide DNA methylation meta-analysis in the brains of suicide completers

Suicide is the second leading cause of death globally among young people representing a significant global health burden. Although the molecular correlates of suicide remains poorly understood, it has been hypothesised that epigenomic processes may play a role. The objective of this study was to identify suicide-associated DNA methylation changes in the human brain by utilising previously published and unpublished methylomic datasets. We analysed prefrontal cortex (PFC, n = 211) and cerebellum (CER, n = 114) DNA methylation profiles from suicide completers and non-psychiatric, sudden-death controls, meta-analysing data from independent cohorts for each brain region separately. We report evidence for altered DNA methylation at several genetic loci in suicide cases compared to controls in both brain regions with suicide-associated differentially methylated positions enriched among functional pathways relevant to psychiatric phenotypes and suicidality, including nervous system development (PFC) and regulation of long-term synaptic depression (CER). In addition, we examined the functional consequences of variable DNA methylation within a PFC suicide-associated differentially methylated region (PSORS1C3 DMR) using a dual luciferase assay and examined expression of nearby genes. DNA methylation within this region was associated with decreased expression of firefly luciferase but was not associated with expression of nearby genes, PSORS1C3 and POU5F1. Our data suggest that suicide is associated with DNA methylation, offering novel insights into the molecular pathology associated with suicidality.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.NA/Fondation Brain Canada (Fondation Neuro Canada) MR/K013807/1/MRC_/Medical Research Council/United Kingdom NIMH 1R21MH094771/U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) MR/K013807/1/Brain and Behavior Research Foundation (Brain & Behavior Research Foundation) MR/K013807/1/RCUK | MRC | Medical Research Foundation NA/Fonds de Recherche du Québec-Société et Culture (FRQSC) R21 MH094771/MH/NIMH NIH HHS/United Statespublished version, accepted version, submitted versio

Major surgery induces acute changes in measured DNA methylation associated with immune response pathways

Surgery is an invasive procedure evoking acute inflammatory and immune responses that can influence risk for postoperative complications including cognitive dysfunction and delirium. Although the specific mechanisms driving these responses have not been well-characterized, they are hypothesized to involve the epigenetic regulation of gene expression. We quantified genome-wide levels of DNA methylation in peripheral blood mononuclear cells (PBMCs) longitudinally collected from a cohort of elderly patients undergoing major surgery, comparing samples collected at baseline to those collected immediately post-operatively and at discharge from hospital. We identified acute changes in measured DNA methylation at sites annotated to immune system genes, paralleling changes in serum-levels of markers including C-reactive protein (CRP) and Interleukin 6 (IL-6) measured in the same individuals. Many of the observed changes in measured DNA methylation were consistent across different types of major surgery, although there was notable heterogeneity between surgery types at certain loci. The acute changes in measured DNA methylation induced by surgery are relatively stable in the post-operative period, generally persisting until discharge from hospital. Our results highlight the dramatic alterations in gene regulation induced by invasive surgery, primarily reflecting upregulation of the immune system in response to trauma, wound healing and anaesthesia.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This work was supported by the Medical Research Council (Grant MR/M008924/1), the Sasakawa Foundation (Butterfield Awards B108) and the UK National Institute for Health Research (NIHR) Exeter Clinical Research Facility (Exeter CRF).Published version, Accepted version, Submitted versio

The CDC Revised Recommendations for HIV Testing: Reactions of Women Attending Community Health Clinics

The purpose of this study was to examine reactions to the Centers for Disease Control and Prevention revised recommendations for HIV testing by women attending community health clinics. A total of 30 women attending three community clinics completed semistructured individual interviews containing three questions about the recommendations. Thematic content analysis of responses was conducted. Results were that all agreed with the recommendation for universal testing. Most viewed opt-out screening as an acceptable approach to HIV testing. Many emphasized the importance of provision of explicit verbal informed consent. The majority strongly opposed the elimination of the requirement for pretest prevention counseling and spontaneously talked about the ongoing importance of posttest counseling. The conclusion was that there was strong support for universal testing of all persons 13 to 64 years old but scant support for the elimination of pretest prevention counseling. In general, respondents believed that verbal informed consent for testing as well as provision of HIV-related information before and after testing were crucial

Leveraging DNA-Methylation Quantitative-Trait Loci to Characterize the Relationship between Methylomic Variation, Gene Expression, and Complex Traits

Characterizing the complex relationship between genetic, epigenetic, and transcriptomic variation has the potential to increase understanding about the mechanisms underpinning health and disease phenotypes. We undertook a comprehensive analysis of common genetic variation on DNA methylation (DNAm) by using the Illumina EPIC array to profile samples from the UK Household Longitudinal study. We identified 12,689,548 significant DNA methylation quantitative trait loci (mQTL) associations (p 60 human traits by using summary-data-based Mendelian randomization (SMR) to identify 1,662 pleiotropic associations between 36 complex traits and 1,246 DNAm sites. We also use SMR to characterize the relationship between DNAm and gene expression and thereby identify 6,798 pleiotropic associations between 5,420 DNAm sites and the transcription of 1,702 genes. Our mQTL database and SMR results are available via a searchable online database as a resource to the research community

Bigmelon:Tools for analysing large DNA methylation datasets

Motivation The datasets generated by DNA methylation analyses are getting bigger. With the release of the HumanMethylationEPIC micro-array and datasets containing thousands of samples, analyses of these large datasets using R are becoming impractical due to large memory requirements. As a result there is an increasing need for computationally efficient methodologies to perform meaningful analysis on high dimensional data. Results Here we introduce the bigmelon R package, which provides a memory efficient workflow that enables users to perform the complex, large scale analyses required in epigenome wide association studies (EWAS) without the need for large RAM. Building on top of the CoreArray Genomic Data Structure file format and libraries packaged in the gdsfmt package, we provide a practical workflow that facilitates the reading-in, preprocessing, quality control and statistical analysis of DNA methylation data. We demonstrate the capabilities of the bigmelon package using a large dataset consisting of 1193 human blood samples from the Understanding Society: UK Household Longitudinal Study, assayed on the EPIC micro-array platform. copy; 2018 The Author(s). Published by Oxford University Press.</p

Genome-wide DNA Methylation Meta-Analysis in the Brains of Suicide Completers

Suicide is the second leading cause of death globally among young people representing a significant global health burden. Although the molecular correlates of suicide remains poorly understood, it has been hypothesised that epigenomic processes may play a role. The objective of this study was to identify suicide-associated DNA methylation changes in the human brain by utilising previously published and unpublished methylomic datasets. We analysed prefrontal cortex (PFC, n = 211) and cerebellum (CER, n = 114) DNA methylation profiles from suicide completers and non-psychiatric, sudden-death controls, meta-analysing data from independent cohorts for each brain region separately. We report evidence for altered DNA methylation at several genetic loci in suicide cases compared to controls in both brain regions with suicide-associated differentially methylated positions enriched among functional pathways relevant to psychiatric phenotypes and suicidality, including nervous system development (PFC) and regulation of long-term synaptic depression (CER). In addition, we examined the functional consequences of variable DNA methylation within a PFC suicide-associated differentially methylated region (PSORS1C3 DMR) using a dual luciferase assay and examined expression of nearby genes. DNA methylation within this region was associated with decreased expression of firefly luciferase but was not associated with expression of nearby genes, PSORS1C3 and POU5F1. Our data suggest that suicide is associated with DNA methylation, offering novel insights into the molecular pathology associated with suicidality