No abstract

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

BACKGROUND Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)–Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. METHODS We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. RESULTS In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen’s d = −0.17, p = .00054), and smaller amygdalae (d = −0.11, p = .025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p < .0063). CONCLUSIONS Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain’s response to trauma.

No abstract

This study used the Multidimensional Personality Questionnaire (MPQ; A. Tellegen, in press) to identify personality-based subtypes of posttraumatic response. Cluster analyses of MPQs completed by combat veterans revealed subgroups that differed on measures relating to the externalization versus internalization of distress. The MPQ profile of the externalizing cluster was defined by low Constraint and Harmavoidance coupled with high Alienation and Aggression. Individuals in this cluster also had histories of delinquency and high rates of substance-related disorder. In comparison, the MPQ profile of the internalizing cluster was characterized by lower Positive Emotionality, Alienation, and Aggression and higher Constraint, and individuals in this cluster showed high rates of depressive disorder. These findings suggest that dispositions toward externalizing versus internalizing psychopathology may account for heterogeneity in the expression of posttraumatic responses, including patterns of comorbidity.

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.

Adverse posttraumatic neuropsychiatric sequelae (APNS) are common among civilian trauma survivors and military veterans. These APNS, as traditionally classified, include posttraumatic stress, post-concussion syndrome, depression, and regional or widespread pain. Traditional classifications have come to hamper scientific progress because they artificially fragment APNS into siloed, syndromic diagnoses unmoored to discrete components of brain functioning and studied in isolation. These limitations in classification and ontology slow the discovery of pathophysiologic mechanisms, biobehavioral markers, risk prediction tools, and preventive/ treatment interventions. Progress in overcoming these limitations has been challenging, because such progress would require studies that both evaluate a broad spectrum of posttraumatic sequelae (to overcome fragmentation) and also perform in-depth biobehavioral evaluation (to index sequelae to domains of brain function). This article summarizes the methods of the Advancing Understanding of RecOvery afteR traumA (AURORA) Study. AURORA conducts a large scale (n = 5,000 target sample) in-depth assessment of APNS development using a state-of-the-art battery of self-report, neurocognitive, physiologic, digital phenotyping, psychophysical, neuroimaging, and genomic assessments, beginning in the early aftermath of trauma and continuing for one year. The goals of AURORA are to achieve improved phenotypes, prediction tools, and understanding of molecular mechanisms to inform the future development and testing of preventive and treatment interventions.

Posttraumatic stress disorder is a serious and often disabling syndrome that develops in response to a traumatic event. Many individuals who initially develop the disorder go on to experience a chronic form of the condition that in some cases can last for many years. Among these patients, psychiatric and medical comorbidities are common, including early onset of age-related conditions such as chronic pain, cardiometabolic disease, neurocognitive disorders, and dementia. The hallmark symptoms of posttraumatic stress-recurrent sensory-memory reexperiencing of the trauma(s)-are associated with concomitant activations of threat- and stress-related neurobiological pathways that occur against a tonic backdrop of sleep disturbance and heightened physiological arousal. Emerging evidence suggests that the molecular consequences of this stress-perpetuating syndrome include elevated systemic levels of oxidative stress and inflammation. In this article we review evidence for the involvement of oxidative stress and inflammation in chronic PTSD and the neurobiological consequences of these processes, including accelerated cellular aging and neuroprogression. Our aim is to update and expand upon previous reviews of this rapidly developing literature and to discuss magnetic resonance spectroscopy as an imaging technology uniquely suited to measuring oxidative stress and inflammatory markers in vivo. Finally, we highlight future directions for research and avenues for the development of novel therapeutics targeting oxidative stress and inflammation in patients with PTSD.