Genomics of Posttraumatic Stress Disorder in Veterans

Background and Objectives Posttraumatic stress disorder (PTSD) is a severe, sometimes disabling, anxiety disorder that can develop after a potentially traumatic event involving actual or threatened death, serious injury, or sexual violation. The diagnosis of PTSD requires symptoms for at least one month from three categories: re-experiencing, avoidance, and increased arousal. In contrast to an acute response to trauma, the stress reactions of persons who develop PTSD do not resolve quickly; symptoms can last for long periods of time and may increase in severity. The rate of PTSD (and consequent disability) is especially high among combat-exposed military Veterans. Studies of Vietnam combat veterans have consistently found a lifetime PTSD prevalence of 25-30% of men, although rates of persistent/chronic PTSD have been somewhat lower (15-20%). Studies of OEF/OIF Army personnel have reported rates of PTSD in the 10% to 15% range following deployment (Thomas et al 2010). These rates are much higher than the rate of PTSD in the general US population, estimated to be about 6.8% (Kessler et al 2005). PTSD has been shown to be influenced genetically, and previous work has identified several possible genes that increase the risk of PTSD. Although several genomewide association studies (GWASs) have been conducted, the corresponding statistical power has been modest, and none included a Veteran-only population. The proposed study will address those deficiencies by conducting a well-powered case-control GWAS study in a large sample of US Veterans with PTSD as "cases" and psychiatrically-healthy Veterans as "controls." Preliminary Data and Research Design The study will use a case-control design nested within the VA Million Veteran Program (MVP), with genotype as the exposure variable and PTSD diagnosis (yes/no) as the outcome variable. The pool of potential PTSD cases will be identified initially based on self-report of a PTSD diagnosis on a previously completed self-report questionnaire collected in MVP, or evidence of a PTSD diagnosis in the VA electronic health record (EHR). Specific validation procedures will narrow the pool to confirmed PTSD cases and controls. Based on available MVP and VA EHR data, the investigators estimate a currently available source population of more than 11,000 confirmed PTSD cases among the approximately 145,000 MVP enrollees to date. By the time this project gets underway, the number of available cases (and controls) will be even higher, due to ongoing enrollment into MVP. Laboratory Methods and Statistical Analyses This PTSD GWAS will compare 10,000 combat-exposed Veterans with PTSD to 10,000 combat-exposed controls. A to-be-selected microarray (see narrative) will be employed that contains approximately 245K genomewide association markers, 250K exonic markers and INDELs, 70K novel loss-of-function SNPs and INDELs, and 115K "custom" markers. Genotypes will be imputed to approximately 1KG for statistical analysis, and up to 50 putatively-associated SNPs that are initially imputed will be genotyped directly in the same sample. Anticipated Results and Relevance Genetic loci affecting combat-related PTSD risk and resilience will be identified, providing important information to inform therapeutic targets related to prevention and treatment.