Document Type

Article

Publication Date

2024

DOI

10.1186/s13148-024-01649-3

Publication Title

Clinical Epigenetics

Volume

16

Pages

38 (1-13)

Abstract

Background

Large-scale cohort and epidemiological studies suggest that PTSD confers risk for dementia in later life but the biological mechanisms underlying this association remain unknown. This study examined this question by assessing the influences of PTSD, APOE ε4 genotypes, DNA methylation, and other variables on the age- and dementia-associated biomarkers Aβ40, Aβ42, GFAP, NfL, and pTau-181 measured in plasma. Our primary hypothesis was that PTSD would be associated with elevated levels of these markers.

Methods

Analyses were based on data from a PTSD-enriched cohort of 849 individuals. We began by performing factor analyses of the biomarkers, the results of which identified a two-factor solution. Drawing from the ATN research framework, we termed the first factor, defined by Aβ40 and Aβ42, "Factor A" and the second factor, defined by GFAP, NfL and pTau-181, "Factor TN." Next, we performed epigenome-wide association analyses (EWAS) of the two-factor scores. Finally, using structural equation modeling (SEM), we evaluated (a) the influence of PTSD, age, APOE ε4 genotype and other covariates on levels of the ATN factors, and (b) tested the mediating influence of the EWAS-significant DNAm loci on these associations.

Results

The Factor A EWAS identified one significant locus, cg13053408, in FANCD2OS. The Factor TN analysis identified 3 EWAS-significant associations: cg26033520 near ASCC1, cg23156469 in FAM20B, and cg15356923 in FAM19A4. The SEM showed age to be related to both factors, more so with Factor TN (β = 0.581, p < 0.001) than Factor A (β = 0.330, p < 0.001). Genotype-determined African ancestry was associated with lower Factor A (β = 0.196, p < 0.001). Contrary to our primary hypothesis, we found a modest negative bivariate correlation between PTSD and the TN factor scores (r = - 0.133, p < 0.001) attributable primarily to reduced levels of GFAP (r = - 0.128, p < 0.001).

Conclusions

This study identified novel epigenetic associations with ATN biomarkers and demonstrated robust age and ancestral associations that will be essential to consider in future efforts to develop the clinical applications of these tests. The association between PTSD and reduced GFAP, which has been reported previously, warrants further investigation.

Rights

© The Authors 2024.

This is a U.S. Government work and not under copyright protection in the U.S., foreign copyright may apply 2024.

This article is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original authors and the source.

The Creative Commons Public Domain Dedication Waiver (CC0 1.0 Universal) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Data Availability

Article states: "Qualified investigators can gain access to study data by contacting Dr. Miller and developing a Data Use Agreement with the PTSD Genetics Data Repository (Miller, PI)."

Original Publication Citation

Miller, M. W., Wolf, E. J., Zhao, X., Logue, M. W., & Hawn, S. E. (2024). An EWAS of dementia biomarkers and their associations with age, African ancestry, and PTSD. Clinical Epigenetics, 16, 1-13, Article 38. https://doi.org/10.1186/s13148-024-01649-3

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