Abstract
BackgroundPrevious studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD).MethodsIn 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).ResultsThe analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10-7, padj = 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 × 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 × 10-5, padj = 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 × 10-6, padj = 0.042).ConclusionsThe 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.
Highlights
Genetic studies of posttraumatic stress disorder (PTSD) diatheses conducted to date have focused primarily on identifying Deoxyribonucleic acid (DNA) variants that confer risk for the development of the disorder through candidate gene or genome-wide association studies (GWASs; see, e.g., [1, 2])
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 suggest that that some
The Aryl-hydrocarbon Receptor Repressor (AHRR) result, involving cg05575921 (Fig. 2b), was noteworthy because this probe was one of the 39 used to compute the DNA methylation (DNAm) smoking score that was included as a covariate in the Epigenome-wide association study (EWAS)
Summary
Genetic studies of posttraumatic stress disorder (PTSD) diatheses conducted to date have focused primarily on identifying DNA variants (e.g., single-nucleotide polymorphisms, SNPs) that confer risk for the development of the disorder through candidate gene or genome-wide association studies (GWASs; see, e.g., [1, 2]). Studies have examined differences between PTSD cases and controls in patterns of gene expression [3] and/or DNA methylation (DNAm [4,5,6];). Hypothesis and mechanism-focused candidate gene studies have identified PTSD-related differences in DNAm levels in genes associated with the hypothalamicpituitary-adrenal (HPA) axis (e.g., ADCYAP1 [9], FKBP5 [10], and NR3C1 [11]), inflammation (e.g., BDNF [4], HTR2A [12] and IL-18 [13]), and neurotransmission (e.g., BDNF [4], HTR2A [14], and HTR3A [15]). Epigenome-wide association studies (EWASs), on the other hand, take a hypothesis-free approach to identifying DNAm loci from across the genome that are statistically associated with the phenotype of interest. Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD)
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