“Genetic and Trauma-Related Risk Factors for PTSD”
Post-traumatic stress disorder (PTSD) is a debilitating syndrome that occurs in only some people after exposure to traumatic events. Both genetic and psychological factors are thought to contribute to the vulnerability towards pathological response to trauma.This project aims to determine the relative contribution of genetic and trauma-related factors to risk for PTSD following trauma. We propose to study stress-related candidate genes that likely play important roles in mediating vulnerability to PTSD. This would be the first study to examine many of these genes that span a variety of functions including monoamine, neurotrophic, and hypothalamic-pituitary axis (HPA) regulation. In addition, we propose to study the interaction of these candidate genes with other known non-genetic risk factors. Finally, our proposal is novel because it will examine PTSD-related neuroendocrine and physiological endophenotypes that likely reflect the action of specific genes more directly than the complex diagnosis of PTSD itself.
This 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 suggest that this population has rates of PTSD rivaling those of Vietnam combat veterans. The focus on this population serves to i) increase our knowledge of this debilitating disorder in an understudied group, ii) increase the feasibility of the study given the high rate of trauma, iii) increase the feasibility of the study by recruiting subjects from their community general medical clinic, and iv) 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.
A. Specific Aims:
- Recruitment: Gather DNA samples from 1300 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 i) recent and ongoing stressors, ii) family psychiatric and stress history, iii) past adult trauma, iv) history of childhood trauma, iv) peri-traumatic emotional response related to index traumas, and iv) 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.
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