STATEMENT OF THE RESEARCH PROBLEM The increased number and length of deployments unique to Operation Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/OIF/OND) Veterans places them at risk for the development of PTSD. While the impact of combat exposure, ongoing stress, lack of social support, and childhood adversity on PTSD is relatively well- established, there is substantial variability in Veterans'response to these stressors that may be due to differences in genetic susceptibility. Moreover, the specific genes that contribute to the development of PTSD remain largely unknown, as does the manner in which these genes might interact with each other and environmental factors to produce and maintain this debilitating condition. Lack of such knowledge is an important problem because it limits our ability to prevent and treat PTSD among returning Veterans. RESEARCH OBJECTIVES The long range goal of the proposed research is to identify the manner in which genes interact with each other and the environment to produce and maintain psychiatric disorders among Veterans. The proposed study will contribute to this goal by using genetic modeling procedures (including haplotype analyses) to examine the effects of two promising candidate genes-the serotonin transporter gene (SLC6A4) and the brain-derived neurotrophic factor (BDNF) gene on PTSD. While previous research with civilians suggests the importance of studying these genes in relation to PTSD, the interactions among SLC6A4, BDNF, and environmental stressors like combat exposure have not been tested among Veterans.
The specific aims of the proposed research are to: (1) Examine the direct effects of combat exposure, ongoing stress, social support, and childhood adversity on PTSD;(2) Examine the direct effects of SLC6A4 and BDNF on PTSD;and (3) Examine whether the effects of combat exposure, ongoing stress, lack of social support, and childhood adversity on PTSD are moderated by SLC6A4 and BDNF variation. To achieve the proposed objectives, a sample of 300 male OEF/OIF/OND Veterans with and without PTSD will be recruited. Standardized clinical interview and self-report data will be collected to assess Veterans'diagnostic status and symptom severity. Combat exposure, stressful life events, social support, and childhood adversity will be assessed via self-report. Blood samples will be collected so that participants can be genotyped for SLC6A4 and BDNF variation. A panel of 24 short tandem repeat loci will also be genotyped to assess and control for potential population stratification. Genetic modeling procedures and latent moderated structural equations will be used to test the hypotheses. TRAINING OBJECTIVES The proposed CDA will provide Dr. Kimbrel with mentored research time so that he can achieve his goal of becoming an independent VA Scientist. Dr. Kimbrel is particularly interested in studying the etiology of PTSD, which is of high relevance to Veterans and the VA research mission. The proposed CDA will provide him with advanced training in psychiatric genetics, statistical genetics, PTSD research methods, ethics, and research administration. In turn, this training will enable him to develop and implement a programmatic line of G x E and G x G research focused on the etiology of PTSD among Veterans.
PTSD represents one of the greatest mental health challenges currently faced by returning Veterans. The proposed research has the potential to positively impact Veterans'health by identifying the combinations of genes and environmental stressors that are most likely to lead to the development of this disabling disorder. In turn, this information can be used to inform prevention and treatment efforts. For example, identification of biological substrates is imperative for the development of novel pharmacological interventions for PTSD. In addition, genetic markers could be used to develop tailored medication regimens for Veterans diagnosed with PTSD based on their genetic profile, resulting in improved treatment outcomes. Genetic markers could also be used to inform preventative practices, such as prescribing medications to high-risk Veterans in a prophylactic manner prior to traumatic exposure (e.g., prior to deployments). Identification of biological markers has the potential to significantly reduce suffering among both Veterans and their loved ones.
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