622 research outputs found
Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide.
This is the final version of the article. Available from Nature Publishing Group via the DOI in this record.Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesised that regulatory genomic processes are involved in the pathology of both MDD and suicidality. In this study, genome-wide patterns of DNA methylation were assessed in depressed suicide completers (n=20) and compared with non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focused on identifying differentially methylated regions (DMRs) associated with suicidal depression and epigenetic variation were explored in the context of polygenic risk scores for major depression and suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed suicide completers and polygenic burden for MDD and suicide attempt. We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite pyrosequencing and replicated in a second set of suicide samples, which is characterised by significant hypomethylation in both cortical brain regions in MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for suicide attempt, but not major depression. Suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Our data suggest that there are coordinated changes in DNA methylation associated with suicide that may offer novel insights into the molecular pathology associated with depressed suicide completers.We are grateful to all of the patients and control subjects who contributed to this
study. The authors would like to acknowledge support of the Brain and Behaviour
Research Foundation through a NARSAD Young Investigator Grant to TMM and from
the UK Medical Research Council (MRC) (grant number MR/K013807/1) to JM. ZK
would like to acknowledge funding from the NIH grant (grant number NIMH
1R21MH094771). The Douglas Bell Canada Brain Bank is supported by the FRQS
through the Quebec Network on Suicide, Mood Disorders and Related Disorders, and
by Brain Canada through an infrastructure grant. We acknowledge Niamh Mullins and
Professor Catherine Lewis, King’s College London, for kindly supplying us with the
suicide attempt GWAS data
Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress disorder
Traumatic stress results in hypothalamic pituitary adrenal (HPA) axis abnormalities and an increased risk to both suicidal behaviors and post-traumatic stress disorder (PTSD). Previous work out of our laboratory identified SKA2 DNA methylation associations with suicidal behavior in the blood and brain of multiple cohorts. Interaction of SKA2 with stress predicted suicidal behavior with ~80% accuracy. SKA2 is hypothesized to reduce the ability to suppress cortisol following stress, which is of potentially high relevance in traumatized populations. Our objective was to investigate the interaction of SKA2 and trauma exposure on HPA axis function, suicide attempt and PTSD. SKA2 DNA methylation at Illumina HM450 probe cg13989295 was assessed for association with suicidal behavior and PTSD metrics in the context of Child Trauma Questionnaire (CTQ) scores in 421 blood and 61 saliva samples from the Grady Trauma Project (GTP) cohort. Dexamethasone suppression test (DST) data were evaluated for a subset of 209 GTP subjects. SKA2 methylation interacted with CTQ scores to predict lifetime suicide attempt in saliva and blood with areas under the receiver operator characteristic curve (AUCs) of 0.76 and 0.73 (95% confidence interval (CI): 0.6–0.92, P=0.003, and CI: 0.65–0.78, P<0.0001) and to mediate the suppression of cortisol following DST (β=0.5±0.19, F=1.51, degrees of freedom (df)=12/167, P=0.0096). Cumulatively, the data suggest that epigenetic variation at SKA2 mediates vulnerability to suicidal behaviors and PTSD through dysregulation of the HPA axis in response to stress
Genome-wide DNA methylation meta-analysis in the brains of suicide completers
This is the final version. Available from Springer Nature via the DOI in this record. 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.Academy of Medical SciencesUK Medical Research CouncilNI
Genetic, environmental and stochastic factors in monozygotic twin discordance with a focus on epigenetic differences
PMCID: PMC3566971This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits
Autism spectrum disorder (ASD) defines a group of common, complex neurodevelopmental disorders. Although the aetiology of ASD has a strong genetic component, there is considerable monozygotic (MZ) twin discordance indicating a role for non-genetic factors. Because MZ twins share an identical DNA sequence, disease-discordant MZ twin pairs provide an ideal model for examining the contribution of environmentally driven epigenetic factors in disease. We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort. This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism
Removing krypton from xenon by cryogenic distillation to the ppq level
The XENON1T experiment aims for the direct detection of dark matter in a
cryostat filled with 3.3 tons of liquid xenon. In order to achieve the desired
sensitivity, the background induced by radioactive decays inside the detector
has to be sufficiently low. One major contributor is the -emitter
Kr which is an intrinsic contamination of the xenon. For the XENON1T
experiment a concentration of natural krypton in xenon Kr/Xe < 200
ppq (parts per quadrillion, 1 ppq = 10 mol/mol) is required. In this
work, the design of a novel cryogenic distillation column using the common
McCabe-Thiele approach is described. The system demonstrated a krypton
reduction factor of 6.410 with thermodynamic stability at process
speeds above 3 kg/h. The resulting concentration of Kr/Xe < 26 ppq
is the lowest ever achieved, almost one order of magnitude below the
requirements for XENON1T and even sufficient for future dark matter experiments
using liquid xenon, such as XENONnT and DARWIN
Search for Two-Neutrino Double Electron Capture of Xe with XENON100
Two-neutrino double electron capture is a rare nuclear decay where two
electrons are simultaneously captured from the atomic shell. For Xe
this process has not yet been observed and its detection would provide a new
reference for nuclear matrix element calculations. We have conducted a search
for two-neutrino double electron capture from the K-shell of Xe using
7636 kgd of data from the XENON100 dark matter detector. Using a
Bayesian analysis we observed no significant excess above background, leading
to a lower 90 % credibility limit on the half-life
yr. We also evaluated the sensitivity of the XENON1T experiment, which is
currently being commissioned, and find a sensitivity of
yr after an exposure of 2 tyr.Comment: 6 pages, 4 figure
Plant Vaccines: An Immunological Perspective.
The advent of technologies to express heterologous proteins in planta has led to the proposition that plants may be engineered to be safe, inexpensive vehicles for the production of vaccines and possibly even vectors for their delivery. The immunogenicity of a variety of antigens of relevance to vaccination expressed in different plants has been assessed. The purpose of this article is to examine the utility of plant-expression systems in vaccine development from an immunological perspective
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