An epigenome-wide association study of posttraumatic stress disorder (PTSD) in US veterans implicates several new DNA methylation loci

This fascinating topic fits perfectly the theme of gene-environment interactions. The environmental “signal” is severe stress, and the response by the genome of some (but not all) individuals is to develop post-traumatic stress disorder (PTSD). In the early 1990s, “a genetic cause of PTSD” was being explored at the University of Cincinnati; “genetics thinking at that time”, of course, was that the trait (disease phenotype) is likely caused by one gene — which we now appreciate was very naïve. ☹ Now we know that multifactorial traits (e.g. PTSD) always reflect the contributions of genetics (i.e. DNA squence differences), epigenetic events (DNA methylation, RNA-interference, histone modulation, chromatin remodeling), environmental effects (life style, smoking), endogenous influences (e.g. cardiopulmonary disease, kidney function status), and each individual’s microbiome [commensal (i.e. long-term biological interaction in which members of one species gain benefits — while those of the other species neither benefit nor are harmed) microbes living in many places within our bodies].

In recent years, studies — using candidate-gene and genome-wide approaches — have focused on epigenetic changes in DNA methylation (DNAm) associated with PTSD. Authors [see attached article] performed an epigenome-wide association study (EWAS) of PTSD in a cohort of military veterans (N = 378 lifetime PTSD cases vs 135 controls), using the Illumina EPIC Methylation BeadChip (which assesses DNAm at >850,000 DNA-methylation sites throughout the genome). This model included covariates for ancestry, cell heterogeneity, gender, age, and a smoking score — based on DNAm at 39 smoking-associated CpGs (regions of DNA where cytosine nucleotide is followed by guanine nucleotide in linear sequence of bases, in the 5’→3′ direction). Authors also examined EPIC-based DNAm data generated from prefrontal cortex (PFC) tissue from the National PTSD Brain Bank (N = 72).

In blood samples, authors discovered one genome-wide significant association with PTSD in the G0S2 (P = 1.2 x 10–7) gene ( “G0/G1 growth switch-2” pertaining to cell cycle); this association was replicated in the independent prefrontal-cortex (PGC)-PTSD-EWAS consortium meta-analysis of military cohorts (P = 0.0024). Authors also observed an association with the smoking-related AHRR (aryl hydrocarbon receptor repressor) gene, evidence suggestive of a smoking-independent effect. The top 100 EWAS loci were then examined in the prefrontal cortex (PFC) data. One of the blood-based PTSD loci, in the CHST11 (carbohydrate sulfotransferase-11) gene — (which was in the top 10 loci in blood, but which did not reach genome-wide significance) — was significantly associated with PTSD in brain tissue. Gene-set-enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO (gene ontology) terms involved in pathogen response, including “response to lipopolysaccharide” (P = 7.0 x 10–6).

For those interested — previous genome-wide association studies (GWAS) have reported PTSD-related differences in DNAm levels in genes associated with the hypothalamic-pituitary-adrenal axis (e.g. ADCYAP1, FKBP5, NR3C1), with inflammation (e.g. BDNF, HTR2A, IL-18), and with neurotransmission (e.g. BDNF, HTR2A, HTR3A) [see Refs 9-14 of attached article]. In contrast, five published PTSD EWAS [see Refs 4-6 & 16, 17 of attached article] have reported single-site associations within the genes ACP5, ANXA2, CLEC9A, TLR8, TPR, BRSK1, DOCK2, LCN8, NGF, LCN8, HIST1H2APS2 (pseudogene), RNF39, ZFP57, CCDC88C, AHRR, and several intergenic loci. For anyone curious as to what these genes represent, please check with the web site .

These GEITP pages suggest that one might be a bit wary of some of the (above) ‘statistically significant loci’ data. Authors (of the present more solid study), however, concluded that their cross-replication — observed in independent cohorts — is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations. Their data also suggest that that some PTSD associations — observed in peripheral tissue — might mirror associations detectable in the brain. 😊


Clin Epigenet Mar 2020; 12: 46

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