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BackgroundEpigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis.ResultsStage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 × 10-08) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region.ConclusionsThis study suggests that the development of combat-related PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent findings suggest the involvement of the immune system through the HLA region and HEXDC, and MAD1L1 which was previously associated with PTSD.

INTRODUCTION: We investigated blood DNA methylation patterns associated with 15 well‐established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. METHODS: We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF‐AD) study using the EPIC array. RESULTS: We identified Bonferroni‐significant differential methylation associated with CSF YKL‐40 (five loci) and neurofilament light chain (NfL; seven loci) levels, with two of the loci associated with CSF YKL‐40 levels correlating with plasma YKL‐40 levels. A co‐localization analysis showed shared genetic variants underlying YKL‐40 DNA methylation and CSF protein levels, with evidence that DNA methylation mediates the association between genotype and protein levels. Weighted gene correlation network analysis identified two modules of co‐methylated loci correlated with several amyloid measures and enriched in pathways associated with lipoproteins and development. DISCUSSION: We conducted the most comprehensive epigenome‐wide association study (EWAS) of AD‐relevant CSF biomarkers to date. Future work should explore the relationship between YKL‐40 genotype, DNA methylation, and protein levels in the brain. Highlights: Blood DNA methylation was assessed in the EMIF‐AD MBD study.Epigenome‐wide association studies (EWASs) were performed for 15 Alzheimer's disease (AD)–relevant cerebrospinal fluid (CSF) biomarker measures.Five Bonferroni‐significant loci were associated with YKL‐40 levels and seven with neurofilament light chain (NfL).DNA methylation in YKL‐40 co‐localized with previously reported genetic variation.DNA methylation potentially mediates the effect of single‐nucleotide polymorphisms (SNPs) in YKL‐40 on CSF protein levels. [ABSTRACT FROM AUTHOR]

Background: Psychosis occurs in 30‐40% of individuals with AD. New insights into disease mechanisms may lead to novel pharmacological targets and treatments. Previous studies have focused on bulk tissue analysis with limited results. Digital spatial profiling (DSP) is a new technique for spatial analysis of RNA or proteins in fixed tissue. It allows quantitative profiling with spatial complexity to be collected from samples in a non‐destructive manner. In this pilot study we used DSP to compare whole transcriptome data in amyloid beta and non‐amyloid beta regions in participants with and without psychosis (AD+P; AD‐P). Method: Six post‐mortem brain samples from prefrontal cortex were provided by the Kings College London Brains for Dementia Research (BDR) brain bank. Frozen and formalin fixed, paraffin embedded (FFPE) sections were supplied in order to test the platform on each type. Psychosis positive and negative groups were selected based on Neuropsychiatric Inventory (NPI) assessments. Samples were hematoxylin and eosin (H&E) stained as well as stained with fluorescent antibodies for AT8, NeuN, SYTO13 and Aβ. Regions of interest (ROIs) are selected based on morphology markers and tissue morphology (see Figure 1 for Amyloid ROI selection). Result: H&E staining revealed the frozen samples to be too badly degraded so the analysis was conducted on FFPE sections. AT8 staining showed widespread tau pathology to the extent that it was not possible to confidently select non‐tau ROIs. Analysis of Aβ plaque containing and Aβ plaque free regions, comparing AD+P and AD‐P groups, found 314 differentially expressed genes in plaque free regions, and 172 differentially expressed genes in plaque containing regions (Figure 2). Of these 172 genes, 28 were not differentially expressed in plaque free regions, forming a plaque‐specific signature of genes differentially expressed in AD+P. Conclusion: This pilot study demonstrates the potential of the NanoString GeoMx™ DSP platform as an innovative spatial transcriptomics methodology for investigating AD+P with the potential to uncover differentially expressed genes that may be missed by bulk RNA sequencing studies. FFPE sections appear to be optimal. Analysing earlier stage disease and more sections per subject may help with better differentiation of tau and non‐tau ROIs. [ABSTRACT FROM AUTHOR]

Background: The onset and progression of Alzheimer's disease (AD) has been widely linked with inflammation both in the periphery and within the brain. Indeed, infections during life can increase the risk of developing dementia and the rate of cognitive decline in AD patients, with many AD sufferers ultimately dying with a systemic infection. One of the aims of this study is to investigate the molecular mechanisms involved in the brain's response to systemic infections in AD through the analysis of gene expression changes. Method: The cohort of patients selected for the study is composed of 204 post‐mortem prefrontal cortex brain samples. The cohort is divided as follows: 58 samples affected by AD and 33 controls, all of whom died with a respiratory infection, and 60 AD patients and 53 controls who did not have an infection at the time of the death. Following RNA sequencing; differential expression analysis, weighted gene correlation network analysis (WGCNA) as well as cell‐type and pathway enrichment analysis were performed. Result: The results of the differential expression analysis indicate that 1185 genes were differentially expressed. The cell‐type enrichment analysis revealed a significant enrichment in microglia, fundamental cells in brain immune response. Pathway enrichment analysis on the differentially expressed genes reported that the top ten enriched pathways were all associated with immune response; examples include "regulation of myeloid leukocytes mediated immunity." A module from WGCNA also exhibited a correlation with both AD and infection. The cell‐enrichment analysis on the genes in this module demonstrated enrichment in oligodendrocytes and astrocytes, which are reported to be involved in immune response. Conclusion: This analysis laid the foundations for further investigations into gene expression changes associated with AD and infection. Future work will include combining this data with miRNA sequencing, DNA methylation and genotyping data from the same individuals to gain a comprehensive overview of the underlying biological mechanisms. [ABSTRACT FROM AUTHOR]