This R01 application proposes a genome-wide association study (GWAS) to probe the hereditary basis for risk or resilience to develop post-traumatic stress disorder (PTSD). Little information is available about factors that explain why some trauma survivors develop stress disorders (up to 15%) and others do not. However, recovery from trauma may be impacted by a web of risk and resilience factors, indexed by genetic, psychological, social/cultural, and biological systems. The goal of this project is to identify such factors by a) studying a prospectively assessed, systematically phenotyped population to discover factors that predict development of PTSD and b) indentifying gene-by-environment interactions. The San Diego Marine Resiliency Study (MRS) is an ongoing, prospective study of >2500 US Marines bound for combat deployment to Iraq or Afghanistan, with the goal to identify factors that predict development of PTSD. Each Marine is evaluated pre-deployment on an array of psychosocial, psychophysiological, and biophysiological phenotypes, and then followed by longitudinal assessments post-deployment. The phenotypes collected were chosen for their potential to serve as 'intermediate'phenotypes for stress-triggered disorders, and include for example startle reactivity, heart rate/blood pressure, and markers of HPA function and catecholamine signaling. Information on environmental risk factors such as past trauma and childhood neglect are collected to identify common experiences that may influence PTSD development. The MRS is thus uniquely suited to identify both genetic and environmental contributions to PTSD symptom development. Data collection of the MRS is funded by the DoD and VA, and will be completed at the start of this proposed funding period, but R01 funding is essential for the implementation of the as-yet un-funded genetic component. The overall guiding hypothesis is that genomic variations give rise to risk/susceptibility traits that, when actuated by the appropriate environmental stimulus, such as combat, give rise to PTSD and other stress- triggered phenotypes. Specifically, this application aims to: 1) Scan the entire genome of ~2500 combat- exposed subjects for genetic variants, 2) Examine the association of genetic variants with PTSD scores, and test for gene-by-environment interactions including combat and other trauma exposure, 3) Test for association of genetic variants with simpler biological traits linked to PTSD vulnerability and its longitudinal changes over time, and thus to build and test genetic risk scores, and 4) Fine-map and replicate findings in other cohorts. We anticipate that the insights gained from this multi-faceted approach will provide a unique opportunity to improve understanding of the genetic contributors to PTSD, and open the way towards novel diagnostic tests and therapeutic approaches to this currently enigmatic and difficult-to-manage condition. Importantly, genome- wide genotype data of a large PTSD cohort is not yet publicly available, and this study thus will generate a rich resource for research on genetic and environmental effects for the neuropsychiatric research community.

Public Health Relevance

Post-traumatic stress disorder (PTSD) poses not only individual suffering, but also a significant burden on the US health care system, with rates to develop PTSD after combat and other trauma exposure around 10-15%. PTSD affects only some of those exposed to trauma, and vulnerability factors are poorly understood. This R01 application seeks to determine genetic contributions to and predictors of the clinical outcome of PTSD, and thus to pave the way for novel diagnostic tests and therapeutic approaches to this difficult-to-manage disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH093500-02
Application #
8305627
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Addington, Anjene M
Project Start
2011-07-25
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$443,316
Indirect Cost
$133,783
Name
University of California San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Bendjilali, Nasrine; Hsueh, Wen-Chi; He, Qimei et al. (2014) Who are the Okinawans? Ancestry, genome diversity, and implications for the genetic study of human longevity from a geographically isolated population. J Gerontol A Biol Sci Med Sci 69:1474-84
Zhang, Kuixing; Deacon, Dekker C; Rao, Fangwen et al. (2014) Human heart rate: heritability of resting and stress values in twin pairs, and influence of genetic variation in the adrenergic pathway at a microribonucleic acid (microrna) motif in the 3'-UTR of cytochrome b561 [corrected]. J Am Coll Cardiol 63:358-68
Nievergelt, Caroline M; Wineinger, Nathan E; Libiger, Ondrej et al. (2014) Chip-based direct genotyping of coding variants in genome wide association studies: utility, issues and prospects. Gene 540:104-9
Agorastos, Agorastos; Pittman, James O E; Angkaw, Abigail C et al. (2014) The cumulative effect of different childhood trauma types on self-reported symptoms of adult male depression and PTSD, substance abuse and health-related quality of life in a large active-duty military cohort. J Psychiatr Res 58:46-54
Scott-Van Zeeland, A A; Bloss, C S; Tewhey, R et al. (2014) Evidence for the role of EPHX2 gene variants in anorexia nervosa. Mol Psychiatry 19:724-32
Eraly, Satish A; Nievergelt, Caroline M; Maihofer, Adam X et al. (2014) Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry 71:423-31
Peng, Qian; Gizer, Ian R; Libiger, Ondrej et al. (2014) Association and ancestry analysis of sequence variants in ADH and ALDH using alcohol-related phenotypes in a Native American community sample. Am J Med Genet B Neuropsychiatr Genet 165B:673-83
Mustapic, Maja; Maihofer, Adam X; Mahata, Manjula et al. (2014) The catecholamine biosynthetic enzyme dopamine ?-hydroxylase (DBH): first genome-wide search positions trait-determining variants acting additively in the proximal promoter. Hum Mol Genet 23:6375-84
Norden-Krichmar, Trina M; Gizer, Ian R; Libiger, Ondrej et al. (2014) Correlation analysis of genetic admixture and social identification with body mass index in a Native American community. Am J Hum Biol 26:347-60
Zhang, Kuixing; Huentelman, Matthew J; Rao, Fangwen et al. (2014) Genetic implication of a novel thiamine transporter in human hypertension. J Am Coll Cardiol 63:1542-55

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