An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci.
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Logue Mark W, Miller Mark W, Wolf Erika J, Huber Bertrand Russ, Morrison Filomene G, Zhou Zhenwei, Zheng Yuanchao, Smith Alicia K, Daskalakis Nikolaos P, Ratanatharathorn Andrew, Uddin Monica, Nievergelt Caroline M, Ashley-Koch Allison E, Baker Dewleen G, Beckham Jean C, Garrett Melanie E, Boks Marco P, Geuze Elbert, Grant Gerald A, Hauser Michael A, Kessler Ronald C, Kimbrel Nathan A, Maihofer Adam X, Marx Christine E, Qin Xue-Jun, Risbrough Victoria B, Rutten Bart P F, Stein Murray B, Ursano Robert J, Vermetten Eric, Vinkers Christiaan H, Ware Erin B, Stone Annjanette, Schichman Steven A, McGlinchey Regina E, Milberg William P, Hayes Jasmeet P, Verfaellie Mieke, Traumatic Stress Brain Study Group
Аннотация
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 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).
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.