An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci

Background Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD). Methods In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72). Results The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 x 10(-7), p(adj) = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 x 10(-6)), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 x 10(-5), p(adj) = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p = 6.97 x 10(-6), p(adj) = 0.042). Conclusions The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.Stress-related psychiatric disorders across the life spa

Distinct functional networks within the cerebellum and their relation to cortical systems assessed with independent component analysis

Cerebellar functional circuitry has been examined in several prior studies using resting fMRI data and seed-based procedures, as well as whole-brain independent component analysis (ICA). Here, we hypothesized that ICA applied to functional data from the cerebellum exclusively would provide increased sensitivity for detecting cerebellar networks compared to previous approaches. Consistency of group-level networks was assessed in two age- and sex-matched groups of twenty-five subjects each. Cerebellum-only ICA was compared to the traditional whole-brain ICA procedure to examine the potential gain in sensitivity of the novel method. In addition to replicating a number of previously identified cerebellar networks, the current approach revealed at least one network component that was not apparent with the application of whole brain ICA. These results demonstrate the gain in sensitivity attained through specifying the cerebellum as a target structure with regard to the identification of robust and reliable networks. The use of similar procedures could be important in further expanding on previously defined patterns of cerebellar functional anatomy, as well as provide information about unique networks that have not been explored in prior work. Such information may prove crucial for understanding the cognitive and behavioral importance of the cerebellum in health and diseas