With terrorism, natural disasters, mass shootings, war and other forms of horror and violence on the rise across the globe, understanding the mental health consequences of these events, and treating survivors, has become a major public health priority. Posttraumatic stress disorder (PTSD) is the most common psychiatric consequence for survivors of such trauma and a serious and potentially disabling condition that affects 8-10% of individuals in the U.S. population at some point during their lifetimes (Kessler et al., 2012;Kessler et al., 1995). In those exposed to intense and repeated trauma, such as military combat, lifetime prevalence is considerably higher (i.e., closer to 20%). Twin studies have shown that a substantial proportion of variation in PTSD risk is attributable to hereditable factors leading investigators to begin to explore the molecular genetic basis of these effects. Unfortunately, results of genetic association studies conducted to date have been inconsistent and the heritability of PTSD remains largely unexplained. Recently, however, our research group published the first genome-wide association study (GWAS) of PTSD which implicated the Retinoic Acid Orphan Receptor Alpha gene (RORA) as a significant risk locus for the development of PTSD after trauma exposure (Logue et al., 2012). The primary finding from that study was subsequently replicated by an independent research group (Amstadter et al., 2013). We believe that the basis for RORA's association with PTSD lies in its role in protecting neurons from the effects of oxidative stress (OXS) and inflammation (INF). Specifically, we hypothesize that individuals who carry the RORA risk variant(s) have a reduced capacity to mount a neuroprotective response to the OXS and INF associated with PTSD. As a result, they are more likely to incur damage to regions of the brain involved in emotion, memory, attention, and other psychiatrically-relevant processes where the loss of neural integrity alters brain function and yields symptoms of the disorder. The primary aim of this study is to test this and related hypotheses using data from the Translational Research Center for Traumatic Brain Injury and Stress Disorders at VA Boston Healthcare System (TRACTS). Specifically, we propose to study the intersection of RORA genotype, other OXS and INF genes, PTSD and other psychopathology, and structural brain parameters using existing genomic data from a high-density gene chip and high resolution structural magnetic resonance imaging (MRI) brain scans from 190 Caucasian OEF/OIF veterans. We will also explore associations between other aspects of psychiatric illness and abnormalities in brain morphology and examine effects of mild Traumatic Brain Injury (mTBI) on these parameters. Evidence in support of our primary hypotheses could pave the way towards the development of medications designed to enhance protective RORA and OXS and INF gene function-and in doing so promote neural resilience in individuals with genetic risk variants.

Public Health Relevance

Posttraumatic stress disorder (PTSD) is a serious and potentially disabling condition that affects 8-10% of individuals in the U.S. population at some point during their lifetimes. Neuroimaging studies suggest that it may also affect the integrity of neural circuits in the brain. This study will examine the role that genes play in protecting brain cells from the damage associated with PTSD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Behavioral Genetics and Epidemiology Study Section (BGES)
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Tuma, Farris K
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Boston University
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Wolf, Erika J; Maniates, Hannah; Nugent, Nicole et al. (2018) Traumatic stress and accelerated DNA methylation age: A meta-analysis. Psychoneuroendocrinology 92:123-134
Wolf, Erika J; Logue, Mark W; Morrison, Filomene G et al. (2018) Posttraumatic psychopathology and the pace of the epigenetic clock: a longitudinal investigation. Psychol Med :1-10
Logue, Mark W; van Rooij, Sanne J H; Dennis, Emily L et al. (2018) Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia. Biol Psychiatry 83:244-253
Miller, M W; Maniates, H; Wolf, E J et al. (2018) CRP polymorphisms and DNA methylation of the AIM2 gene influence associations between trauma exposure, PTSD, and C-reactive protein. Brain Behav Immun 67:194-202
Sadeh, Naomi; Spielberg, Jeffrey M; Logue, Mark W et al. (2018) Linking genes, circuits, and behavior: network connectivity as a novel endophenotype of externalizing. Psychol Med :1-9
Miller, Mark W; Lin, Alex P; Wolf, Erika J et al. (2018) Oxidative Stress, Inflammation, and Neuroprogression in Chronic PTSD. Harv Rev Psychiatry 26:57-69
Hayes, J P; Reagan, A; Logue, M W et al. (2018) BDNF genotype is associated with hippocampal volume in mild traumatic brain injury. Genes Brain Behav 17:107-117
Logue, Mark W; Smith, Alicia K; Wolf, Erika J et al. (2017) The correlation of methylation levels measured using Illumina 450K and EPIC BeadChips in blood samples. Epigenomics 9:1363-1371
Miller, Danielle R; Logue, Mark W; Wolf, Erika J et al. (2017) Posttraumatic stress disorder symptom severity is associated with reduced default mode network connectivity in individuals with elevated genetic risk for psychopathology. Depress Anxiety 34:632-640
Hayes, Jasmeet P; Logue, Mark W; Sadeh, Naomi et al. (2017) Mild traumatic brain injury is associated with reduced cortical thickness in those at risk for Alzheimer's disease. Brain 140:813-825

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