Genomic Approaches to Identify Novel Molecular and Pathway Targets for PTSD

Lee, Hyunhwa

Abstract

PTSD affects both mental and physical health across the lifespan in ways that the disease has so much heterogeneity in terms of its diverse subtypes, different symptom profiles, and high comorbidities with other disorders, which impedes effective preventive treatments. Childhood adversity plays another big role to create heterogeneity in PTSD onset and progress. PTSD is also highly comorbid with other emotional disorders and/or physical symptoms. The association between childhood adversity and adulthood PTSD can be explained by the fact that psychological behaviors are both a result of genetic and biological factors (nature) and life experiences (nurture). Clinical models also explains such a significant association, as shown in the Diathesis-Stress Theory, Stress Sensitization Model, or Resilience Model. Although these psychosocial models provide clinical guides for PTSD treatment and therapy, evidence is lacking to show how such models are associated with bio-physiological or genetic mechanism of stress response. The multifactorial nature of PTSD is unlikely due to any single pattern of genetic mutations but it instead may involve numerous genetic alterations including epigenetic modifications. Both animal models and clinical studies have shown that early childhood trauma results in biological changes in the individuals that increase their vulnerability to PTSD later in life following adult stress and trauma. This project therefore consists of a series of clinical and translational studies for evaluating psychological, behavioral risk factors, including previous trauma, as well as genetic and epigenetic molecular targets and biological pathways for the development of PTSD and other comorbid psychiatric (e.g., depression) and physical (e.g., pain and sleep disturbances) symptoms. First, a big pool of military participants for transcriptome, epigenome and proteome analyses were from the Madigan Army Medical Center (CNRM-funded project;MAMC-FWA00003277, NIH-FWA00002830). The participant enrollment was completed for the first phase of this project in 9/2012, resulting in a sample of 117 military personnel seeking care for a sleep disorder. We elected to continue recruitment of participants and to develop a second phase to the study. The institutional review board approval of reinitiating this project was approved on 8/13/2013. All participants in this study underwent a polysomonographic sleep evaluation and had blood collected for biomarker measurement which includes transcriptome, proteome, and epigenome (i.e., DNA methylation). Participants are seen at baseline and 6 weeks to 3 months following this. We use follow-up data to examine changes in symptoms with standard of care interventions. Accomplishments include data-based publications as well as presentations by this group. These include the following: A. Publications: 1. Mysliwiec V, Gill J, Lee H, Baxter T, Pierce R, Barr TL, Krakow B, Roth BJ (2013) Sleep Disorders in US Military Personnel: A High Rate of Comorbid Insomnia and Obstructive Sleep Apnea. Chest 144:549-57. 2. Gill J, Saligan L, Lee H, Rotolo S, Szanton S (2013) Women in recovery from PTSD have similar inflammation and quality of life as non-traumatized controls. J Psychosom Res 74:301-6. 3. Gill J, Lee H, Baxter T, Pierce R, Barr TL, Krakow B, Mysliwiec V. Adherence with CPAP in OSA Patients is Linked to Increases in IGF-1 and Reductions in Symptoms of PTSD. (Accepted Psychosomatic Medicine) B. Conference Presentations: 1. Lee H, Wang D, Pierce R, Baxter T, Dionne R, Kim H, Mysliwiec V, &Barr TL. (November 8, 2012). Gene expression profiling in post-traumatic stress disorder, mild traumatic brain injury, depression and sleep disorder among redeployed military personnel. 62nd Annual Meeting of the American Society of Human Genetics, San Francisco, California. 2. Lee H, Wang D, Xiao W, Gill J, Mysliwiec V, Barr TL, Baxter T, Pierce R, &Kim H. (April, 2013). Whole-genome DNA methylation pattern changes over 3 months in post-traumatic stress disorder. National Capital Area TBI Symposium, Bethesda, Maryland. In addition, a secondary data analysis with genetic (SNP), psychosocial, and medical record data was conducted in a candidate gene association study with saliva DNA samples from a group of 326 pregnant women (NIH OHSRP #11838). This sample was from a parent study that was a prospective observational study of the effect of PTSD on perinatal outcomes among 1,581 women in southeast Michigan (R01 NR 008767-03S2, PI Seng). In the current analysis, the participants were trauma-exposed controls and lifetime PTSD-diagnosed cases, stratified by European- and African-American ancestry. The major findings have been summarized in a manuscript, which will be soon submitted to a peer-reviewed journal. Based on the finding linking OXTR with dissociation, somatization, and interpersonal sensitivity, OXTR may be a useful biomarker, along with other known stress-related genes (ADCYAP1R1 (PACAP), CRHR2, FKBP5, COMT, BDNF, and ADRB2), to distinguish the subtypes of PTSD, in related to childhood maltreatment history. A prospective cohort data of 17 subjects with axonal injury after mild traumatic brain injury (TBI) in student athletes were from the emergency department of the University of Rochester Medical Center (URMC) (NIH OHSRP #11658). A total of 44 white cell samples from the 17 subjects were used for gene expression microarray analysis. Preliminary analysis reveals gene transcripts specific to post-injury that are associated with CDK5 (FOSB, KRAS, PRKAR1A) and Atherosclerosis (IL8, IFNG, CCR2) signaling. Additional data collection has been currently on going. Transcriptome profiling and DNA methylation analysis will be conducted when all data collection is completed. Lastly, a secondary data analysis with behavioral variables was conducted to examine the relationships among childhood adversity and adult psychological outcomes. The subjects were 206 Korean Americans living in the Midwestern U.S., and they responded to a web-based survey on childhood experiences and current mental health. Path analysis results revealed sense of belonging as the most powerful, and resilience as the second important factor, resisting depressive symptoms associated with parental alcoholism. In addition, different types of childhood domestic violence experiences were significantly associated with adult resilience, sense of belonging, and depression. Relevant publications include the following: 1. Lee H, Williams RA (2013) Effects of parental alcoholism, sense of belonging, and resilience on depressive symptoms: a path model. Subst Use Misuse 48:265-73. 2. Lee HL (2013) Childhood domestic violence, alcoholic parents, and adult psychological features. Journal of Korean Academy of Psychiatric Mental Health Nursing, in press.