Ratanatharathorn A., Boks M.P., Maihofer A.X., , … Uddin M., Nievergelt C.M., Smith A.K. Epigenome-wide association of PTSD from heterogeneous cohorts with a common multi-site analysis pipeline. Am J Med Genet B Neuropsychiatr Genet (2017)
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 × 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 bloodbased 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).
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.
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