Traumatic stress and accelerated DNA methylation age: A meta-analysis
Introduction
Traumatic stress (e.g., psychiatric symptoms related to traumatic experiences) may precipitate a host of negative outcomes inclusive of psychological and medical conditions (Schnurr et al., 2000; Afari et al., 2014). Theory (Miller and Sadeh, 2014; Lohr et al., 2015; Williamson et al., 2015) and empirical research (Roberts et al., 2017, Li et al., 2017; Wolf et al., 2016, Wolf et al., 2017) suggest that traumatic stress may also advance the pace of cellular aging such that it exceeds that of chronological aging and this may potentially lead to, or be a marker for, negative health outcomes (Horvath, 2013).
There are highly reliable age-related changes in DNA methylation (DNAm) throughout the epigenome (Christensen et al., 2009). Recent research has capitalized on these associations and on the substantial information available from state-of-the-art DNAm arrays, capturing methylation levels at hundreds of thousands of CpG (Cytosine-phosphate-Guanine) loci using just a single beadchip and a small amount of DNA, to develop methylation-based estimates of chronological age. Specifically, Hannum et al. (2013) developed a DNAm age algorithm derived from whole blood that was based on 71 probes (89 in the “all data” model) and it correlated with chronological age at r = 0.96. Independently, Horvath (2013) identified 353 DNAm loci that when combined into a weighted summary score also evidenced very strong correlations (r = 0.96) with chronological age across multiple tissues. Support for the utility and validity of DNAm age is evident in research demonstrating that DNAm age estimates that are higher than expected given chronological age (i.e., “accelerated DNAm age”) are associated with age-related disorders and mortality (Chen et al., 2016; Christiansen et al., 2016; Horvath et al., 2015; Levine et al., 2015; Marioni et al., 2016; Marioni et al., 2015). Collectively, this suggests that accelerated DNAm age may be a biomarker for a generalized pathological cellular aging process, with a variety of environmental conditions and diseases associated with this basic epigenetic “clock.”
Emerging research raises the possibility that traumatic stress may be associated with advanced DNAm age, though results to date have been mixed. Specifically, Wolf et al., 2016, Wolf et al., 2017 reported that symptoms of posttraumatic stress disorder (PTSD) were associated with DNAm age acceleration (relative to chronological age) per the Hannum, but not the Horvath (Wolf et al., 2016), algorithm in two samples of predominately male U.S. military veterans (sample sizes ranged from 281 to 339). In contrast, in a Dutch sample of 96 male military veterans, Boks et al. (2015) reported that PTSD was negatively associated with Horvath DNAm age estimates over time, while combat trauma was positively associated with Horvath DNAm age. In that study, the relationship between DNAm age and chronological age was not factored in to the definition of age acceleration. In a largely female civilian sample (n = 392), Zannas et al. (2015) found no evidence of an association between childhood trauma exposure or PTSD and accelerated Horvath DNAm age relative to chronological age. However, the authors did report an association between personal life stressors and advanced Horvath DNAm age, particularly among older participants. The variability in the approach to measuring DNAm age across these studies (e.g., Horvath versus Hannum metrics; inconsistent use of operational definitions that model the relationship between DNAm age and chronological age) and the variability in results across studies to date make it difficult to discern a clear pattern of association between traumatic stress and accelerated aging in DNAm.
Given this, the aim of this study was to bring the strengths of the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup (Ratanatharathorn et al., 2017) to bear on the evaluation of the association between traumatic stress and accelerated DNAm age using data from nine cohorts encompassing 2186 subjects. The PGC (Sullivan et al., 2017), which began in 2007 and added the PTSD Working Group in 2012, represents the largest consortium in biological psychiatry; this study used a subset of PGC-affiliated datasets with relevant data.
The specific aims of the study were to: (1) evaluate DNAm age and DNAm age acceleration1 in association with key demographic (i.e., sex, ancestry, age) and cellular variables (i.e., white blood cell proportions); (2) examine associations between trauma exposure and PTSD with accelerated DNAm age; and (3) examine demographic variables that might moderate the association between traumatic stress and accelerated DNAm age. Given that PTSD-related accelerated DNAm age has only been observed with the Hannum et al. DNAm age algorithm (Wolf et al., 2016, Wolf et al., 2017), we hypothesized that PTSD diagnosis and severity would be associated with accelerated Hannum et al. DNAm age, but we investigated Horvath DNAm age in parallel. These goals were accomplished by deploying a standardized script and instructions to individual investigators with relevant data who participate in the PGC PTSD Epigenetics Workgroup and then meta-analyzing results across cohorts.
Section snippets
Participants
Table 1 lists the individual cohorts included in the meta-analysis and key demographic and methodological details of the studies. There were seven military samples. These included: (1) the National Center for PTSD cohort (NCPTSD; Logue et al., 2013), a sample of 465 white, non-Hispanic trauma-exposed male and female veterans from mixed war eras and a subset of their trauma-exposed spouses2
Associations between DNAm age and chronological age across Hannum and Horvath models
The meta-correlation between Hannum DNAm age and chronological age was r = 0.87 (SD = 0.09). The meta-correlation between Horvath DNAm age and chronological age was r = 0.87 (SD = 0.07; Table 2). In general, the strength of this correlation was associated with the variance in chronological age in each sample. This effect is shown in Fig. 1, which plots the association between the variance in age in each sample and the correlation between DNAm age and chronological age for both DNAm age
Discussion
This was the largest and most demographically heterogeneous evaluation of the associations between trauma exposure, PTSD, and accelerated aging in DNAm, spanning nine studies and over 2000 participants. Results of meta-analyses suggested that both childhood trauma exposure (when assessed with the CTQ) and lifetime PTSD severity (assessed with the CAPS for the majority of studies with lifetime PTSD severity data), were associated with accelerated epigenetic aging. Associations between lifetime
Disclosures
In the past 3 years, Dr. Kessler received support for his epidemiological studies from Sanofi Aventis; was a consultant for Johnson & Johnson Wellness and Prevention, Sage Pharmaceuticals, Shire, Takeda; and served on an advisory board for the Johnson & Johnson Services Inc. Lake Nona Life Project. Kessler is a co-owner of DataStat, Inc., a market research firm that carries out healthcare research.
Conflict of interest
All other authors report no financial conflicts of interest relevant to this work.
Acknowledgements
The Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup is supported by the U.S. Army Medical Research and Materiel Command and the National Institute of Mental Health (NIMH; R01MH108826).
This work was supported in part by: Merit Review Award Number I01 CX-001276-01 to EJW from the United States (U.S.) Department of Veterans Affairs Clinical Sciences R&D (CSR&D) Service, National Institute On Aging of the National Institutes of Health under Award Number R03AG051877-02S1 to EJW,
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