Traumatic stress and accelerated DNA methylation age: A meta-analysis

Highlights

• Meta-analysis suggests lifetime PTSD severity associated with advanced epigenetic age.

• Childhood trauma exposure also associated with advanced epigenetic age.

• These effects evident for Hannum but not Horvath epigenetic age algorithm.

• Sex and white blood cell counts also associated with advanced epigenetic age.

• Results highlight importance of studying health consequences of traumatic stress.

Abstract

Background

Recent studies examining the association between posttraumatic stress disorder (PTSD) and accelerated aging, as defined by DNA methylation-based estimates of cellular age that exceed chronological age, have yielded mixed results.

Methods

We conducted a meta-analysis of trauma exposure and PTSD diagnosis and symptom severity in association with accelerated DNA methylation age using data from 9 cohorts contributing to the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (combined N = 2186). Associations between demographic and cellular variables and accelerated DNA methylation age were also examined, as was the moderating influence of demographic variables.

Results

Meta-analysis of regression coefficients from contributing cohorts revealed that childhood trauma exposure (when measured with the Childhood Trauma Questionnaire) and lifetime PTSD severity evidenced significant, albeit small, meta-analytic associations with accelerated DNA methylation age (ps = 0.028 and 0.016, respectively). Sex, CD4T cell proportions, and natural killer cell proportions were also significantly associated with accelerated DNA methylation age (all ps < 0.02). PTSD diagnosis and lifetime trauma exposure were not associated with advanced DNA methylation age. There was no evidence of moderation of the trauma or PTSD variables by demographic factors.

Conclusions

Results suggest that traumatic stress is associated with advanced epigenetic age and raise the possibility that cells integral to immune system maintenance and responsivity play a role in this. This study highlights the need for additional research into the biological mechanisms linking traumatic stress to accelerated DNA methylation age and the importance of furthering our understanding of the neurobiological and health consequences of PTSD.

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.