1. An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci.
- Author
-
Logue MW, Miller MW, Wolf EJ, Huber BR, Morrison FG, Zhou Z, Zheng Y, Smith AK, Daskalakis NP, Ratanatharathorn A, Uddin M, Nievergelt CM, Ashley-Koch AE, Baker DG, Beckham JC, Garrett ME, Boks MP, Geuze E, Grant GA, Hauser MA, Kessler RC, Kimbrel NA, Maihofer AX, Marx CE, Qin XJ, Risbrough VB, Rutten BPF, Stein MB, Ursano RJ, Vermetten E, Vinkers CH, Ware EB, Stone A, Schichman SA, McGlinchey RE, Milberg WP, Hayes JP, and Verfaellie M
- Subjects
- Basic Helix-Loop-Helix Transcription Factors blood, Case-Control Studies, Cell Cycle Proteins blood, Epigenesis, Genetic, Female, Frontal Lobe chemistry, Genetic Predisposition to Disease, Humans, Male, Oligonucleotide Array Sequence Analysis, Repressor Proteins blood, Stress Disorders, Post-Traumatic blood, United States, Basic Helix-Loop-Helix Transcription Factors genetics, Cell Cycle Proteins genetics, DNA Methylation, Genome-Wide Association Study methods, Repressor Proteins genetics, Stress Disorders, Post-Traumatic genetics, Sulfotransferases genetics, Veterans
- Abstract
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 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.- Published
- 2020
- Full Text
- View/download PDF