Genetic and Trauma Related Risk Factors for PTSD

grady_sideThis project aims to determine the relative contribution of genetic and trauma-related risk factors for Posttraumatic Stress Disorder (PTSD) in a cross-sectional study of a highly traumatized, low socioeconomic status, minority urban population. Although some level of fear and stress is normal following a traumatic experience, understanding the etiology of PTSD requires knowing why chronic pathological symptoms do not occur in all who experience trauma. Individuals appear to have different vulnerabilities for subsequent response to traumatic stress. It is now commonly accepted that PTSD results from an interaction of predisposing genetic and environmental risks that enhance the likelihood of a pathological stress response and fear memory following severe trauma. However, almost nothing is known of the nature of the genetic contribution(s) and how they interact with other risk factors.

Project Description

We will examine non-psychiatric patients from the General Medical Clinics at Grady Memorial Hospital in Atlanta. Our pilot data suggests that over 80% of this population has suffered significant trauma and approximately 30% has PTSD. We will examine three independent factors that contribute to the relative risk for PTSD following trauma: genotype polymorphism, lifetime history of trauma, and peri-traumatic emotional response to the PTSD-related event. Genetic risk factors include described polymorphisms that have been shown to contribute to the development of psychopathology in other stress-related psychiatric disorders, including monoamine related genes (5HTT, DBH, DAT, and COMT), brain-derived neurotrophic factor (BDNF), and genes involved in HPA axis regulation (GR, CRF-R1, FKBP5). Lifetime history of trauma includes childhood trauma and total lifetime trauma. Emotional response to the trauma includes subjective trauma severity as well as peri-traumatic dissociation. Covariates that will be examined include family psychiatric history, substance abuse and dependence, and comorbid psychiatric diagnoses. The primary dependent variables include presence or absence of PTSD diagnosis and PTSD severity. By examining identified candidate genes, known trauma history risk factors, and PTSD diagnosis as well as its component traits, this study will further the understanding of PTSD. Through a greater understanding of the vulnerability factors, both genetic and environmental, that contribute to pathological fear and stress following a trauma, this work will further the development of model systems as well as potentially provide novel intervention, diagnostic, and treatment approaches for this debilitating disorder.

The Study

The study is designed as a cross-sectional analysis of inner city, low socioeconomic status, primarily African-American subjects that are patients at a general medical clinic at Grady Hospital in Atlanta. Our data suggests that this population has rates of PTSD rivaling those of Vietnam combat veterans. The focus on this population serves to 1) increase our knowledge of this debilitating disorder in an understudied group, 2) increase the feasibility of the study given the high rate of trauma, 3) increase the feasibility of the study by recruiting subjects from their community general medical clinic, and 4) increase the power of the study by studying a group with relatively homogeneous socioeconomic status, which has been previously shown to be an important predictor of PTSD following trauma. In response to prior critiques, we have expanded our investigative team to include experts in genetics and statistical genetics. We have also conducted expanded preliminary studies to demonstrate our ability to perform the proposed work.

We Hypothesize:

  1. that we will find significant associations for some or all of these known stress-related genetic polymorphisms with the presence of PTSD or associated endophenotypic markers (avoidant, intrusive, or hyperarousal symptoms; acoustic startle, elevated heart rate, or dysregulated HPA axis), and that there will be a dosage effect such that greater ‘loading’ of high-risk alleles will increase the likelihood of PTSD or associated markers.
  2. that history of childhood trauma, total number of lifetime traumatic experiences and peri-traumatic emotional responses will be associated with the presence of PTSD or associated markers, and that there will also be a dosage effect such that greater exposure to these risk factors will increase the likelihood of PTSD or associated markers.
  3. that gene x environment interactions occur such that the combination of genetic and trauma history risk factors increases likelihood of development of PTSD or associated markers.

Specific Aims:

  • Recruitment: Gather DNA samples from unrelated individuals from the population served by the Grady Hospital Primary Care medical clinics, in Atlanta, Georgia. These subjects will be assessed for:
    • Trauma and stress exposure and risk factors including:
      • recent and ongoing stressors
      • family psychiatric and stress history
      • past adult trauma
      • history of childhood trauma
      • peri-traumatic emotional response related to index traumas
      • post-traumatic stress disorder
    • Co-morbid diagnosis of current and past depression, substance abuse, and psychosis.
  • Environmental factors: Determine the contribution of prior trauma history, peri-traumatic emotional response, family history and home environment, and resiliency to the presence of PTSD and PTSD severity in this population.
  • Genetic factors: Determine contribution of monoamine (5HTT, DAT, COMT, DBH), neurotrophic (BDNF), and HPA axis-related (GR, CRF-R1, FKBP5) genetic polymorphisms to the presence of PTSD in a socially and economically homogenous population that has experienced high levels of trauma.
    • Examine relationships between candidate polymorphisms and PTSD diagnosis with quantitative measures of symptomatology (CAPS score) and separately with categorical measures (CAPS, SCID)
    • Examine relationship between monoamine-related polymorphisms and acoustic startle measures
    • Examine relationship between the HPA axis-related polymorphisms and HPA measures.
  • Gene X Environment Interaction: Assess the direct and interactional effects of candidate genes with prior trauma history and peri-traumatic emotional response on biological markers associated with PTSD, diagnosis of PTSD, and PTSD symptom severity.