Whole-Genome DNA Methylation Status Associated with Clinical PTSD Measures of OIF/OEF Veterans
Journal Article - Open Access
Integrative Systems Biology, US Army Center for Environmental Health Research Frederick United States
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Emerging knowledge suggests that post-traumatic stress disorder PTSD pathophysiology is linked to the patients epigenetic changes, but comprehensive studies examining genome-wide methylation have not been performed. In this study, we examined genome-wide DNA methylation in peripheral whole blood in combat veterans with and without PTSD to ascertain differentially methylated probes. Discovery was initially made in a training sample comprising 48 male Operation Enduring Freedom OEFOperation Iraqi Freedom OIF veterans with PTSD and 51 ageethnicitygender-matched combat-exposed PTSD-negative controls. Agilent whole-genome array detected 5600 differentially methylated CpG islands CpGI annotated to 2800 differently methylated genes DMGs. The majority 84.5 of these CpGIs were hypermethylated in the PTSD cases. Functional analysis was performed using the DMGs encoding the promoter-bound CpGIs to identify networks related to PTSD. The identified networks were further validated by an independent test set comprising 31 PTSD 29 PTSD veterans. Targeted bisulfite sequencing was also used to confirm the methylation status of 20 DMGs shown to be highly perturbed in the training set. To improve the statistical power and mitigate the assay bias and batch effects, a union set combining both training and test set was assayed using a different platform from Illumina. The pathways curated from this analysis confirmed 65 of the pool of pathways mined from training and test sets. The results highlight the importance of assay methodology and use of independent samples for discovery and validation of differentially methylated genes mined from whole blood. Nonetheless, the current study demonstrates that several important epigenetically altered networks may distinguish combat-exposed veterans with and without PTSD.
- Military Forces and Organizations