ABSTRACT: Characterization of Whole Genome DNA Methylation Profile Associated with Post-Traumatic Stress Disorder in OIF/OEF Veterans [bisulfite-converted DNA]
Project description:The biological underpinnings of post-traumatic stress disorder (PTSD) have not been fully elucidated. Previous work suggests that alterations in the immune system are characteristic of the disorder. Identifying the biological mechanisms by which such alterations occur could provide fundamental insights into the etiology and treatment of PTSD. Here we identify specific epigenetic profiles underlying immune system changes associated with PTSD. Using blood samples (n=100) obtained from an ongoing, prospective epidemiologic study in Detroit, the Detroit Neighborhood Health Study (DNHS), we applied methylation microarrays to assay CpG sites from over 14,000 genes among 23 PTSD-affected and 77 PTSD-unaffected individuals. We show that immune system functions are significantly overrepresented among the annotations associated with genes uniquely unmethylated among those with PTSD. We further demonstrate that genes whose methylation levels are significantly and negatively correlated with traumatic burden show a similar strong signal of immune function among the PTSD-affected. The observed epigenetic variability in immune function by PTSD is corroborated using an independent biological marker of immune response to infection, cytomegalovirus—a typically latent herpesvirus whose activity was significantly higher among those with PTSD. These results provide the first report of peripheral epigenomic and CMV profiles associated with mental illness and suggest a new biological model of PTSD etiology in which an externally experienced traumatic event induces downstream alterations in immune function by reducing methylation levels of immune-related genes. Bisulfite conversion of whole blood-derived DNA samples was performed using the EZ-96 DNA methylation kit from Zymo Research. One microgram (μg) of each sample (including controls) was subjected to bisulfite conversion following manufacturer’s recommended protocol. 100 samples were analyzed of which 23 are PTSD affected and 77 are PTSD-unaffected. There were four technical replicates comprised of duplicate samples of two randomly selected individuals from the n=100 and duplicate samples of the control human methylated and unmethylated DNA.
Project description:Emerging knowledge suggests that post-traumatic stress disorder (PTSD) is causally associated with epigenetic changes although its molecular underpinnings are still largely elusive. We postulate that differentially methylated probes mined from peripheral whole blood could be candidates for potential PTSD diagnostic signatures. Working within the Systems Biology PTSD Biomarker Consortium (SBPBC), we investigated a training set comprising of 48 PTSD male veterans (CAPS > 40) and 51 age/ethnicity matched controls (CAPS < 20). Agilent whole genome array detected ~5,600 differentially methylated CpG islands (CpGI) annotated to ~2,800 differentially methylated genes (DMG). The majority (84.5%) of these DMGs was hypermethylated in PTSD veterans. Thereof ~30% promoter-bound DMGs were used for functional analysis. Taking cues from the clinical information, the curated networks were enlisted into four major clusters, namely PTSD-associated complications, PTSD-relevant endocrine signaling, nervous system development and nervous system functions. Enduring impacts of PTSD was manifested by differentially methylated genes enriching networks associated with LTP, fear memory architecture and complications linked to insulin resistance and innate immunity. These networks were further validated by an independent test set comprising of 31/29 PTSD+/- veteran selected using aforementioned screening protocol. Two independent assay platforms presented technical validations. Probing the combined 83/83 PTSD+/- cohort, whole genome array from Illumina, Inc. validated most of the networks of interest. Methylation statuses of eight DMGs relevant to PTSD and comorbidities were confirmed by targeted bisulfite sequencing. This list presents a potential set of PTSD biomarkers of translational potential.
Project description:Emerging knowledge suggests that post-traumatic stress disorder (PTSD) is causally associated with epigenetic changes although its molecular underpinnings are still largely elusive. We postulate that differentially methylated probes mined from peripheral whole blood could be candidates for potential PTSD diagnostic signatures. Working within the Systems Biology PTSD Biomarker Consortium (SBPBC), we investigated a training set comprising of 48 PTSD male veterans (CAPS > 40) and 51 age/ethnicity matched controls (CAPS < 20). Agilent whole genome array detected ~5,600 differentially methylated CpG islands (CpGI) annotated to ~2,800 differentially methylated genes (DMG). The majority (84.5%) of these DMGs was hypermethylated in PTSD veterans. Thereof ~30% promoter-bound DMGs were used for functional analysis. Taking cues from the clinical information, the curated networks were enlisted into four major clusters, namely PTSD-associated complications, PTSD-relevant endocrine signaling, nervous system development and nervous system functions. Enduring impacts of PTSD was manifested by differentially methylated genes enriching networks associated with LTP, fear memory architecture and complications linked to insulin resistance and innate immunity. These networks were further validated by an independent test set comprising of 31/29 PTSD+/- veteran selected using aforementioned screening protocol. Two independent assay platforms presented technical validations. Probing the combined 83/83 PTSD+/- cohort, whole genome array from Illumina, Inc. validated most of the networks of interest. Methylation statuses of eight DMGs relevant to PTSD and comorbidities were confirmed by targeted bisulfite sequencing. This list presents a potential set of PTSD biomarkers of translational potential.
Project description:Background: Schizophrenia is a severe neuropsychiatric disorder that is hypothesized to result from disturbances in early brain development, and there is mounting evidence to support a role for developmentally-regulated epigenetic variation in the molecular etiology of the disorder. Here, we describe a systematic study of schizophrenia-associated methylomic variation in the adult brain and its relationship to changes in DNA methylation across human fetal brain development. Results: We profile methylomic variation in matched prefrontal cortex and cerebellum brain tissue from schizophrenia patients and controls, identifying disease-associated differential DNA methylation at multiple loci, particularly in the prefrontal cortex, and confirming these differences in an independent set of adult brain samples. Our data reveal discrete modules of co-methylated loci associated with schizophrenia that are enriched for genes involved in neurodevelopmental processes and include loci implicated by genetic studies of the disorder. Methylomic data from human fetal cortex samples, spanning 23 to 184 days post-conception, indicates that disease-associated differentially methylated positions are significantly enriched for loci at which DNA methylation is dynamically altered during human fetal brain development. Conclusions: Our data support the hypothesis that schizophrenia has an important early neurodevelopmental component, and suggest that epigenetic mechanisms may mediate these effects. 33 post-mortem brain (prefrontal cortex) samples (18 schizophrenia cases and 15 controls) were obtained from Douglas Bell-Canada Brain Bank (DBCBB), Montreal, Canada. Bisulfite converted DNA from these samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip v1.0.
Project description:This project aims to characterize the transgenerational genomic impact of genocide exposure and post-traumatic stress disorder (PTSD) in women survivors of the Rwandan genocide and their offspring.
Project description:Genome wide DNA methylation profiling in the whole blood samples of healthy controls and major depression disorder (MDD) patients who have never been treated with depression medication. The Illumina Infinium 450k Human DNA methylation Beadchip can assay over 480K CpG sites with bisulfite-converted genomic DNA and has been widely used in methylome-wide association studies (MWAS). Samples included 40 healthy controls and 40 MDD patients who have never been treated with depression medication.