Faculty Bibliography

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

The therapeutic application of human-animal interaction has gained interest recently. One form this interest takes is the use of service dogs as complementary treatment for veterans with Post-Traumatic Stress Disorder (PTSD). Many reports on the positive effect of PTSD Service Dogs (PSDs) on veterans exist, though most are indirect, anecdotal, or based on self-perceived welfare by veterans. They therefore only give a partial insight into PSD effect. To gain a more complete understanding of whether PSDs can be considered an effective complementary treatment for PTSD, a scoping literature review was performed on available studies of PSDs. The key search words were 'dog', 'canine', 'veteran', and 'PTSD'. This yielded 126 articles, of which 19 matched the inclusion criteria (six empirical studies). Recurrent themes in included articles were identified for discussion of methodology and/or results. It was found that results from most included studies were either applicable to human-animal interaction in general or other types of service animals. They therefore did not represent PSDs specifically. Studies which did discuss PSDs specifically only studied welfare experience in veterans, but used different methodologies. This lead us to conclude there is currently no undisputed empirical evidence that PSDs are an effective complementary treatment for veterans with PTSD other than reports on positive welfare experience. Additionally, the lack of development standardization and knowledge regarding welfare of PSDs creates risks for both human and animal welfare. It is therefore recommended that a study on the effect of PSDs be expanded to include evaluation methods besides self-perceived welfare of assisted humans. Future studies could include evaluations regarding human stress response and functioning, ideally conducted according to validated scientific methodologies using objective measurement techniques to identify the added value and mechanisms of using PSDs to assist treatment of PTSD in humans.

Compelling evidence suggests that epigenetic mechanisms such as DNA methylation play a role in stress regulation and in the etiologic basis of stress related disorders such as Post traumatic Stress Disorder (PTSD). Here we describe the purpose and methods of an international consortium that was developed to study the role of epigenetics in PTSD. Inspired by the approach used in the Psychiatric Genomics Consortium, we brought together investigators representing seven cohorts with a collective sample size of N = 1147 that included detailed information on trauma exposure, PTSD symptoms, and genome-wide DNA methylation data. The objective of this consortium is to increase the analytical sample size by pooling data and combining expertise so that DNA methylation patterns associated with PTSD can be identified. Several quality control and analytical pipelines were evaluated for their control of genomic inflation and technical artifacts with a joint analysis procedure established to derive comparable data over the cohorts for meta-analysis. We propose methods to deal with ancestry population stratification and type I error inflation and discuss the advantages and disadvantages of applying robust error estimates. To evaluate our pipeline, we report results from an epigenome-wide association study (EWAS) of age, which is a well-characterized phenotype with known epigenetic associations. Overall, while EWAS are highly complex and subject to similar challenges as genome-wide association studies (GWAS), we demonstrate that an epigenetic meta-analysis with a relatively modest sample size can be well-powered to identify epigenetic associations. Our pipeline can be used as a framework for consortium efforts for EWAS.

Several cross-sectional studies have demonstrated the relevance of DNA methylation of the glucocorticoid receptor exon 1F region (GR-1F) for trauma-related psychopathology. We conducted a longitudinal study to examine GR-1F methylation changes over time in relation to trauma exposure and the development of post-deployment psychopathology. GR-1F methylation (52 loci) was quantified using pyrosequencing in whole blood of 92 military men 1 month before and 6 months after a 4-month deployment period to Afghanistan. GR-1F methylation overall (mean methylation and the number of methylated loci) and functional methylation (methylation at loci associated with GR exon 1F expression) measures were examined. We first investigated the effect of exposure to potentially traumatic events during deployment on these measures. Subsequently, changes in GR-1F methylation were related to changes in mental health problems (total Symptom Checklist-90 score) and posttraumatic stress disorder (PTSD) symptoms (Self-Report Inventory for PTSD). Trauma exposure during deployment was associated with an increase in all methylation measures, but development of mental health problems 6 months after deployment was only significantly associated with an increased functional methylation. Emergence of post-deployment PTSD symptoms was not related to increased functional methylation over time. Pre-deployment methylation levels did not predict post-deployment psychopathology. To our knowledge, this is the first study to prospectively demonstrate trauma-related increases in GR-1F methylation, and it shows that only increases at specific functionally relevant sites predispose for post-deployment psychopathology.

It is clinically well known that olfactory intrusions in PTSD can be a disabling phenomena due to the involuntary recall of odor memories. Odorants can trigger involuntary recall of emotional memories as well have the potential to help diminishing emotional arousal as grounding stimuli. Despite major advances in our understanding of the function of olfactory system, the study of the relation of olfaction and emotional memory is still relatively scarce. Odor memory is long thought to be different than other types of memories such as verbal or visual memories, being more strongly engraved and more closely related to strong emotions. Brain areas mediating smell memory including orbitofrontal cortex and other parts of medial prefrontal cortex, hippocampus and amygdala, have been implicated in learning and memory and are part of a neural circuitry that is involved in PTSD. The olfactory cortex itself also plays an important role in emotional processing. Clinical observations support the notion that odor-evoked memories can play a role in the symptomatology of PTSD. This paper reviews a re-emerging body of science linking odor processing to emotional processing in PTSD using the calming and grounding effect of odors as well as the use of odors in augmented exposure therapy. This results in converging evidence that olfaction is an excellent model for studying many questions germane to the field of human emotional memory processing.

Background: Post-traumatic stress disorder (PTSD) results from trauma, but not all individuals develop PTSD after trauma. Differences in susceptibility to PTSD may be related to epigenetic differences between cases and trauma-exposed controls that can provide insight into the biological processes underlying PTSD and may serve as biological indicators of PTSD risk or resilience. Methods: The PGC-PTSD Epigenetics Workgroup combined epigenome-wide data from a diverse group of military and civilian studies to conduct a cross-sectional meta-analysis of current PTSD in >445 cases and >700 trauma-exposed controls. For all samples, DNA methylation was measured in whole blood using the Infinium HumanMethylation450 BeadChip. A common pipeline was developed for quality control, data normalization and association testing. Using this pipeline, EWAS was performed on each cohort followed by meta-analysis using inverse normal p-value combination and false discovery rate (FDR) estimation. Results: There were substantial differences in the results from each cohort. No CpG site remained significant after correction for multiple testing, but the top results included CpG sites (7.7e-7

EMBASE:72256553

ISSN: 0006-3223

CID: 2103582