Genomics of Posttraumatic Stress Disorder in Veterans

NCT ID: NCT02256644

Last Updated: 2024-10-03

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

20000 participants

Study Classification

OBSERVATIONAL

Study Start Date

2013-12-01

Study Completion Date

2024-09-30

Brief Summary

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Posttraumatic Stress Disorder (PTSD), as a common and serious mental health condition, affects about 25% of all military personnel that have served in combat. People suffering from PTSD may experience traumatic flashbacks, trouble sleeping, and problems in their relationships. This study is intended to help identify genes that influence and increase the risk of PTSD, to improve ways of detecting and treating the condition in the future.

Previous research has studied genes that increase the risk of PTSD, but none of these have included a Veteran-only population. The current study focuses on US Veterans, utilizing the VA Million Veteran Program (MVP) database of approximately 300,000 participants as of August 2014. In this context, participants with PTSD are referred to as "cases" and Veterans without PTSD are referred to as "controls."

This project will be done in three stages. The first stage will look at MVP-obtained data and electronic health record (EHR) data to implement methods for identifying combat-exposed case patients with PTSD and combat-exposed control patients without PTSD. The second stage will assemble and validate a study population of 20,000 participants "including 10,000 combat-exposed Veterans with PTSD as cases and 10,000 combat-exposed Veterans without PTSD as controls. The third stage will conduct genetic analyses ("genotyping") comparing the cases to controls, to identify genes associated with increased risk of developing the condition.

Detailed Description

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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.

Conditions

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PTSD

Study Design

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Observational Model Type

CASE_CONTROL

Study Time Perspective

OTHER

Study Groups

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Million Veteran Program (MVP) participants

Veterans who are currently enrolled in the Million Veteran Program.

No interventions assigned to this group

Eligibility Criteria

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Inclusion Criteria

* Combat-exposed Veterans who participated in the Million Veteran Program.

Exclusion Criteria

* schizophrenia
* bipolar disorder
Minimum Eligible Age

18 Years

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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VA Office of Research and Development

FED

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Murray B Stein, MD MPH

Role: STUDY_CHAIR

VA San Diego Healthcare System, San Diego, CA

Joel Gelernter, MD

Role: STUDY_CHAIR

VA Connecticut Healthcare System West Haven Campus, West Haven, CT

Locations

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VA San Diego Healthcare System, San Diego, CA

San Diego, California, United States

Site Status

Countries

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United States

References

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Austin-Zimmerman I, Levey DF, Giannakopoulou O, Deak JD, Galimberti M, Adhikari K, Zhou H, Denaxas S, Irizar H, Kuchenbaecker K, McQuillin A; Million Veteran Program; Concato J, Buysse DJ, Gaziano JM, Gottlieb DJ, Polimanti R, Stein MB, Bramon E, Gelernter J. Genome-wide association studies and cross-population meta-analyses investigating short and long sleep duration. Nat Commun. 2023 Sep 28;14(1):6059. doi: 10.1038/s41467-023-41249-y.

Reference Type DERIVED
PMID: 37770476 (View on PubMed)

Radhakrishnan K, Aslan M, Harrington KM, Pietrzak RH, Huang G, Muralidhar S, Cho K, Quaden R, Gagnon D, Pyarajan S, Sun N, Zhao H, Gaziano M, Concato J, Stein MB, Gelernter J. Genomics of posttraumatic stress disorder in veterans: Methods and rationale for Veterans Affairs Cooperative Study #575B. Int J Methods Psychiatr Res. 2019 Mar;28(1):e1767. doi: 10.1002/mpr.1767. Epub 2019 Feb 14.

Reference Type DERIVED
PMID: 30767326 (View on PubMed)

Related Links

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Other Identifiers

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575B

Identifier Type: -

Identifier Source: org_study_id

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