Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR

Abstract

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program

“…We also remind readers that the present analyses rested solely on GWAS, thereby limiting inquiry to common genetic variants (to MAF 0.01, which still capture significant heritable variance) and that roles for rare variants and structural variation should also be explored. Epigenetic factors almost certainly also play a role in a disorder such as PTSD 10 , 73 , which has traumatic stress as its precursor. Many other functional genomics tools can and should be brought to bear on the study of PTSD, expanding the scope of inquiry to encompass a holistic, integrative functional genomic analysis 74 of this common, serious, and yet still poorly understood and inadequately treated neuropsychiatric disorder.…”

Targeting the Aryl Hydrocarbon Receptor Signaling Pathway in Breast Cancer Development

“…The IDO-Kyn-AhR signaling pathway has been shown to mediate immunosuppression involving Tregs and tumor-associated macrophages, which can be reversed by AhR inhibition ( 48 ). Interestingly, a recent meta-analysis across military and civilian cohorts indicates that lower AhRR methylation correlates with lower levels of Kyn ( 49 ) suggesting that higher AhRR activity may regulate the level of Kyn. Consequently, the IDO-Kyn-AhR signaling pathway provides a new target in cancer immunotherapy as discussed recently ( 50 ) and AhRR may provide an important tool to inhibit this pathway ( Figure 8 ).…”

Immune system regulation and role of the human leukocyte antigen in posttraumatic stress disorder

“…Functional annotation cluster analyses of uniquely unmethylated genes are enriched for inflammatory response, immune response, and innate immune response pathways in PTSD cases ( Uddin et al, 2010 ). Individuals with PTSD have increased methylation at a CpG site located in Toll-like receptor 8 ( TLR8 ) ( Smith et al, 2011 ), and decreased methylation at CpG sites located in dedicator of cytokinesis 2 ( DOCK2 ) ( Mehta et al, 2017 ), nuclear factor of activated T-cells ( NFATC4 ) ( Hammamieh et al, 2017 ), IL12B ( Bam et al, 2016b ) and aryl hydrocarbon receptor repressor ( AHRR ) ( Logue et al, 2020 ; Smith et al, 2020 ). Prospective studies investigating longitudinal methylation changes associated with PTSD implicated methylation changes in HEXDC and HLA-DPB1 ( Snijders et al, 2020 ), as well as enrichment in IL17 signaling pathway ( Rutten et al, 2018 ).…”