Traumatic stress and human DNA methylation: a critical review

Vinkers, Christiaan H.; Kalafateli, Aimilia Lydia; Rutten, Bart P. F.; Kas, Martien; Kaminsky, Zachary; Turner, Jonathan D.; Boks, Marco P.

doi:10.2217/epi.15.11

Cited by 97 publications

(80 citation statements)

References 87 publications

(118 reference statements)

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“…Gestational depression during pregnancy associated with a lower birth weight (OR 3.6, 95 % CI 1.1–11.4), obesity, as well as cardiovascular disorders and diabetes in later life (Fig. 1) [37, 38]. This was accompanied by higher MEG3 methylation levels (2.4 %) and decreased methylation of IGF2 (−1.6 %) compared to children with normal birth weight [37].…”

Section: Environmental Influence On Phenotype Diversity: a Role For Smentioning

confidence: 99%

DNA methylation: conducting the orchestra from exposure to phenotype?

2016

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DNA methylation, through 5-methyl- and 5-hydroxymethylcytosine (5mC and 5hmC), is considered to be one of the principal interfaces between the genome and our environment, and it helps explain phenotypic variations in human populations. Initial reports of large differences in methylation level in genomic regulatory regions, coupled with clear gene expression data in both imprinted genes and malignant diseases, provided easily dissected molecular mechanisms for switching genes on or off. However, a more subtle process is becoming evident, where small (<10 %) changes to intermediate methylation levels are associated with complex disease phenotypes. This has resulted in two clear methylation paradigms. The latter “subtle change” paradigm is rapidly becoming the epigenetic hallmark of complex disease phenotypes, although we are currently hampered by a lack of data addressing the true biological significance and meaning of these small differences.Our initial expectation of rapidly identifying mechanisms linking environmental exposure to a disease phenotype led to numerous observational/association studies being performed. Although this expectation remains unmet, there is now a growing body of literature on specific genes, suggesting wide ranging transcriptional and translational consequences of such subtle methylation changes. Data from the glucocorticoid receptor (NR3C1) has shown that a complex interplay between DNA methylation, extensive 5′UTR splicing, and microvariability gives rise to the overall level and relative distribution of total and N-terminal protein isoforms generated. Additionally, the presence of multiple AUG translation initiation codons throughout the complete, processed mRNA enables translation variability, hereby enhancing the translational isoforms and the resulting protein isoform diversity, providing a clear link between small changes in DNA methylation and significant changes in protein isoforms and cellular locations. Methylation changes in the NR3C1 CpG island alters the NR3C1 transcription and eventually protein isoforms in the tissues, resulting in subtle but visible physiological variability.This review addresses the current pathophysiological and clinical associations of such characteristically small DNA methylation changes, the ever-growing roles of DNA methylation and the evidence available, particularly from the glucocorticoid receptor of the cascade of events initiated by such subtle methylation changes, as well as addressing the underlying question as to what represents a genuine biologically significant difference in methylation.

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Section: Environmental Influence On Phenotype Diversity: a Role For Smentioning

confidence: 99%

DNA methylation: conducting the orchestra from exposure to phenotype?

2016

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“…In order to explore potential gene–environment interaction, epigenetics offers promising new routes. In particular, epigenetics in stress research and related psychopathologies has generated novel findings that remain to be replicated in large-scale datasets 6. Methylation of the promoter of the oxytocin receptor gene (OXTR) has been implicated in stress and emotional regulation in health and disease,7 8 as well as in social cognition 9.…”

Section: Introductionmentioning

confidence: 99%

Increased methylation of the oxytocin receptor gene in motor functional neurological disorder: a preliminary study

Apazoglou

Adouan

Aubry

et al. 2017

J Neurol Neurosurg Psychiatry

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“…DNA methylation is an important epigenetic mechanism that is influenced by genetic and environmental factors (Malan-Muller et al, 2014), and reflects the transcriptional status of a particular gene (Schubeler, 2015). DNA methylation studies therefore have great potential to increase our understanding of how the interaction between an individual's genetic background and traumatic stress exposure results in the development of PTSD (Vinkers et al, 2015a). Kaminsky and colleagues recently proposed the spindle and kinetochore associated protein 2 (SKA2) gene (Chr17:59110368) as a blood-based DNA methylation biomarker for suicide (Guintivano et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

SKA2 Methylation is Involved in Cortisol Stress Reactivity and Predicts the Development of Post-Traumatic Stress Disorder (PTSD) After Military Deployment

Boks

Rutten

Geuze

et al. 2015

Neuropsychopharmacol

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Genomic variation in the SKA2 gene has recently been identified as a promising suicide biomarker. In light of its role in glucocorticoid receptor transactivation, we investigated whether SKA2 DNA methylation influences cortisol stress reactivity and is involved in the development of post-traumatic stress disorder (PTSD). Increased SKA2 methylation was significantly associated with lower cortisol stress reactivity in 85 healthy individuals exposed to the Trier Social Stress Test (B = − 173.40, t = − 2.324, p-value = 0.023). Next, we observed that longitudinal decreases in SKA2 methylation after deployment were associated with the emergence of post-deployment PTSD symptoms in a Dutch military cohort (N = 93; B = − 0.054, t = − 3.706, p-value = 3.66 × 10 − 4 ). In contrast, exposure to traumatic stress during deployment by itself resulted in longitudinal increases in SKA2 methylation (B = 0.037, t = 4.173, p-value = 6.98 × 10 − 5 ). Using predeployment SKA2 methylation levels and childhood trauma exposure, we found that the previously published suicide prediction rule significantly predicted post-deployment PTSD symptoms (AUC = 0.66, 95% CI: 0.53-0.79) with an optimal sensitivity of 0.81 and specificity of 0.91. Permutation analysis using random methylation loci supported these findings. Together, these data establish the importance of SKA2 for cortisol stress responsivity and the development of PTSD and provide further evidence that SKA2 is a promising biomarker for stress-related disorders including PTSD.

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Traumatic stress and human DNA methylation: a critical review

Cited by 97 publications

References 87 publications

DNA methylation: conducting the orchestra from exposure to phenotype?

DNA methylation: conducting the orchestra from exposure to phenotype?

Increased methylation of the oxytocin receptor gene in motor functional neurological disorder: a preliminary study

SKA2 Methylation is Involved in Cortisol Stress Reactivity and Predicts the Development of Post-Traumatic Stress Disorder (PTSD) After Military Deployment

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