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Activity of DNA methyltransferases (DNMTs), the enzymes that catalyze DNA methylation, is dynamically regulated in the brain. DNMT inhibitors alter DNA methylation globally in the brain and at individual neural plasticity-associated genes, but how DNMT inhibitors centrally influence lipopolysaccharide (LPS)-induced neuroinflammation is not known. We investigated whether the DMNT inhibitor, zebularine, would alter sickness behavior, DNA methylation of the promoter and expression of inflammatory genes in hippocampus and microglia. Contrary to our hypothesis that zebularine may exaggerate LPS-induced sickness response and neuroinflammation, adult mice treated with an intracerebroventricular (ICV) injection of zebularine prior to LPS had surprisingly faster recovery of burrowing behavior compared to mice treated with LPS. Further, genes of inflammatory markers, epigenetic regulators, and the microglial sensory apparatus (i.e., the sensome) were differentially expressed by zebularine alone or in combination with LPS. Bisulfite pyrosequencing revealed that ICV zebularine led to decreased DNA methylation of two CpG sites near the proximal promoter alone or in combination with LPS. Zebularine treated mice still exhibited decreased DNA methylation 48 h after treatment when LPS-induced sickness behavior as well as hippocampal and microglial gene expression were similar to control mice. Taken together, these data suggest that decreased DNA methylation, specifically of the promoter region, with a DNMT inhibitor in the brain disrupts molecular mechanisms of neuroinflammation.

DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3′ un-translated region of DICER1 , rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway. DICER1 is required for the maturation of miRNAs which regulate expression of thousands of genes. Here the authors show significantly reduced levels of DICER1 in individuals having post-traumatic stress disorder and comorbid depression suggestive of a role in the molecular mechanism of the condition.

Background Poor family emotional health (FEH) during childhood is prevalent and impactful, and likely confers similar neurodevelopmental risks as other adverse social environments. Pointed FEH study efforts are underdeveloped, and the mechanisms by which poor FEH are biologically embedded are unclear. The current exploratory study examined whether variability in 5-methyl-cytosine (5mC) and fronto-limbic grey matter volume may represent pathways through which FEH may become biologically embedded. Results In 98 university students aged 18–22 years, retrospective self-reported childhood FEH was associated with right hemisphere hippocampus ( b  = 10.4, p  = 0.005), left hemisphere amygdala ( b  = 5.3, p  = 0.009), and right hemisphere amygdala ( b  = 5.8, p  = 0.016) volumes. After pre-processing and filtering to 5mC probes correlated between saliva and brain, analyses showed that childhood FEH was associated with 49 5mC principal components (module eigengenes; MEs) ( p range  = 3 × 10 –6 to 0.047). Saliva-derived 5mC MEs partially mediated the association between FEH and right hippocampal volume (Burlywood ME indirect effect b  = − 111, p  = 0.014), and fully mediated the FEH and right amygdala volume relationship (Pink4 ME indirect effect b  = − 48, p  = 0.026). Modules were enriched with probes falling in genes with immune, central nervous system (CNS), cellular development/differentiation, and metabolic functions. Conclusions Findings extend work highlighting neurodevelopmental variability associated with adverse social environment exposure during childhood by specifically implicating poor FEH, while informing a mechanism of biological embedding. FEH-associated epigenetic signatures could function as proxies of altered fronto-limbic grey matter volume associated with poor childhood FEH and inform further investigation into primarily affected tissues such as endocrine, immune, and CNS cell types.

Nature Communications 6: Article number: 10106 (2015); Published: 3 December 2015; Updated: 3 March 2016 The original version of this Article contained an error in the spelling of the author Jennifer S. Stevens, which was incorrectly given as Jennifer J. Stevens. Furthermore, in Fig. 5, the titles for panels a and b were inadvertently switched.

Childhood maltreatment (CM) is known to increase susceptibility to depression later in life; and, although depression is also associated with epigenetic changes at HPA axis genes, the molecular mechanisms contributing to increased CM-depression risk remain poorly understood.

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24–71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10−8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further.

There is a well-established negative association of educational attainment (EA) and other traits related to cognitive ability with posttraumatic stress disorder (PTSD), but the underlying mechanisms are poorly understood. To investigate the association of PTSD with traits related to EA. Genetic correlation, polygenic risk scoring, and mendelian randomization (MR) were conducted including 23 185 individuals with PTSD and 151 309 control participants from the Psychiatric Genomics Consortium for PTSD and up to 1 131 881 individuals assessed for EA and related traits from UK Biobank, 23andMe, and the Social Science Genetic Association Consortium. Data were analyzed from July 3 through November 19, 2018. Genetic correlation obtained from linkage disequilibrium score regression, phenotypic variance explained by polygenic risk scores, and association estimates from MR. Summary association data from multiple genome-wide association studies were available for a total of 1 180 352 participants (634 391 [53.7%] women). Posttraumatic stress disorder showed negative genetic correlations with EA (rg = -0.26; SE = 0.05; P = 4.60 × 10-8). Mendelian randomization analysis, conducting considering a random-effects inverse-variance weighted method, indicated that EA has a negative association with PTSD (β = -0.23; 95% CI, -0.07 to -0.39; P = .004). Investigating potential mediators of the EA-PTSD association, propensity for trauma exposure and risk-taking behaviors were observed as risk factors for PTSD independent of EA (trauma exposure: β = 0.37; 95% CI, 0.19 to 0.52; P = 2.57 × 10-5; risk-taking: β = 0.76; 95% CI, 0.38 to 1.13; P = 1.13 × 10-4), while income may mediate the association of EA with PSTD (MR income: β = -0.18; 95% CI, -0.29 to -0.07; P = .001; MR EA: β = -0.23; 95% CI, -0.39 to -0.07; P = .004; multivariable MR income: β = -0.32; 95% CI, -0.57 to 0.07; P = .02; multivariable MR EA: β = -0.04; 95% CI, -0.29 to 0.21; SE, 0.13; P = .79). Large-scale genomic data sets add further evidence to the negative association of EA with PTSD, also supporting the role of economic status as a mediator in the association observed.

Abstract Background Poor family emotional health (FEH) during childhood is prevalent and impactful, and likely confers similar neurodevelopmental risks as other adverse social environments. Pointed FEH study efforts are underdeveloped, and the mechanisms by which poor FEH are biologically embedded are unclear. The current exploratory study examined whether variability in DNA methylation (DNAm) and fronto-limbic grey matter volume may represent pathways through which FEH may become biologically embedded. Results Self-reported childhood FEH was nominally associated with right hemisphere hippocampus (b=10.4, p=0.005), left hemisphere amygdala (b=5.3, p=0.009), and right hemisphere amygdala (b=5.8, p=0.016) volumes. Childhood FEH was also nominally associated with 49 DNAm MEs (prange=3×10−6 to 0.047). After limiting analyses to probes correlated between saliva and brain, saliva-derived DNAm MEs partially mediated the association between FEH and right hippocampal volume (Burlywood ME indirect effect b=-111, p=0.014), and fully mediated the FEH and right amygdala volume relationship (Pink4 ME indirect effect b=-48, p=0.026). Modules were enriched with probes falling in genes with immune, CNS, and metabolic functions. Conclusions Findings extend work highlighting neurodevelopmental variability associated with adverse social environment exposure during childhood by specifically implicating poor FEH, while informing a mechanism of biological embedding. FEH-associated epigenetic signatures could function as proxies of altered fronto-limbic grey matter volume associated with poor childhood FEH and inform further investigation into primarily affected tissues such as endocrine, immune, and CNS cell types. Competing Interest Statement The authors have declared no competing interest.

Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson's Disease gene, PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.