Monoamine Transporters Genotypes: Risk of PTSD and Related Comorbidities

Background: Post-traumatic Stress Disorder (PTSD), a debilitating condition that develops following exposure to trauma, is highly prevalent in military personnel and veterans due to high risk of trauma exposure in combat. Trauma exposure, as an environmental insult, is necessary, but itself is not sufficient to cause PTSD, since not everyone exposure to trauma develops PTSD. Brain dopamine (DAT) and serotonin (5-HTT) transporter play a critical role in the regulation of stress related psychological and behavioral functions. Genetic polymorphisms that affect 5-HTT and DAT function, such as the 5' promote polymorphism in the 5-HTT gene (SLC6A4)(5-HTTlpr) and 3' -untranslated region (UTR)-40 bp-variable number tandem repeat (VNTR)of DAT gene (SLC6A3), could influence individual susceptibility to trauma-related psychopathology. Objective/Hypothesis: The objective of this application is to investigated the relationship between SLC6A3/SLC6A4 and the mental health of veterans exposed to high levels of combat stress, specifically focusing on PTSD symptoms, related comorbidities, and treatment outcome. The central hypothesis is that specific genetic variants that adversely affect serotonin and dopamine neurotransmission constitute a risk for the emergence of PTSD and related comorbid symptoms after trauma exposure; and, some of these variants may further influence PTSD and related response. Specific Objectives: (1) To determine specific 5-HTTLPR genotype involvement in PTSD symptomatology, (2) to determine influence of combined SLC6A3/SLC6A4 genotypes on PTSD with substance dependence, (3)to identify 5 HTTLPR alleles that affect PTSD symptomatology and treatment outcome, and (4)to identify additional SLC6A3/SLC6A4 alleles associated with PTSD and related comorbidities. Study Design: We have generated some preliminary data supporting our hypothesis by examining 5-HTTLPR and the 3'-UTR-VNTR of SLC6A3 genotypes in 109 combat veterans with and without PTSD. In this proposal, we will expand on these findings by recruiting 300 veterans exposed to sufficient combat stress defined by Combat Exposure Scale(CES) score of \>10 and who qualify for DSM-IV category A PTSD diagnostic criteria, including approximately 150 veterans with PTSD veterans with PTSD defined using DSM-IV diagnostic criteria, Clinician Administered PTSD Scale (CAPS) score \>45 and 150 healthy combat-exposed veterans as defined by a CAPS score \<15. We will first apply a newly developed extreme discordant phenotype (EDP) method to examine how 5-HTTLPR and 3'-UTR-VNTR genotypes affect trauma related psychopathology in combat veterans only with the highest (\>45)and lowest (\<15) CAPS scores. Secondly, single nucleotide polymorphisms (SNPs)will be examined across both genes and assessed for relatedness to PTSD susceptibility or resistance. Further analyses of relationship of these polymorphisms with comorbidities will also be performed. Thirdly, a pharmacogenetic trail (using sertraline as a therapeutic agent) will be applied to assess how gene variants influence PTSD treatment outcome. To Safeguard against population stratification, a genome control method will be applied in all the genetic analyses.