Largest genome-wide association studies of PTSD to date identify two gene markers linked to military personnel who develop mental disorder.
In an extensive genetic analysis of more than 13,000 U.S. Army soldiers, researchers have identified two genetic variants that show genome-wide significant associations with lifetime post-traumatic stress disorder (PTSD). These findings, from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS), point to specific loci that may contribute to PTSD susceptibility in military populations and suggest biological links between PTSD and certain inflammatory conditions.
The U.S. Department of Veterans Affairs estimates that 11 to 20 percent of veterans who served in Afghanistan and Iraq will develop PTSD, with even higher rates reported among Vietnam-era veterans. In the general U.S. population, lifetime PTSD prevalence is roughly 7 to 8 percent. Understanding genetic influences on PTSD could improve early identification of at-risk individuals and inform biological pathways relevant to prevention and treatment.
Investigators from the University of California San Diego School of Medicine, Veterans Affairs San Diego Healthcare System, Uniformed Services University, and multiple collaborating institutions performed two coordinated genome-wide association studies (GWAS) using DNA and clinical assessments collected from consenting soldiers. A GWAS scans many genetic markers across the genome to identify variants associated with a specific disorder—here, lifetime DSM-IV PTSD—by comparing affected individuals to trauma-exposed controls who did not develop PTSD.
The first GWAS analyzed 3,167 PTSD cases and 4,607 trauma-exposed controls enrolled in the New Soldier Study (NSS). The second analyzed 947 PTSD cases and 4,969 trauma-exposed controls from the Pre/Post Deployment Study (PPDS). The primary analyses focused on lifetime PTSD diagnoses compared to trauma-exposed controls without lifetime PTSD, and analytic models accounted for ancestry groups and cumulative trauma exposure.
Two loci emerged with genome-wide significance in the NSS sample. In African-American soldiers, a variant in the gene ANKRD55 on chromosome 5 (rs159572) was associated with increased PTSD risk, and this association remained significant after adjusting for the total number of traumatic exposures. ANKRD55 has been implicated in prior studies of autoimmune and inflammatory disorders, including multiple sclerosis, type 2 diabetes, celiac disease, and rheumatoid arthritis. In European-American soldiers, a separate significant signal appeared on chromosome 19 near the gene ZNF626 (rs11085374).
These associations were not consistently replicated across both cohorts or across all ancestry groups. The corresponding single-nucleotide polymorphisms (SNPs) did not show the same significant associations in the PPDS sample, nor did they reach significance in trans-ancestral meta-analyses. SNP-based heritability estimates for PTSD were not statistically significant in these data, indicating that larger samples and additional studies will be required to capture the complex genetic architecture of PTSD.
Although the study found no robust genetic correlations between PTSD and six major psychiatric disorders or nine immune-related disorders overall, analyses did show evidence of pleiotropy—shared genetic influences—between PTSD and rheumatoid arthritis, and, to a lesser extent, psoriasis. This overlap supports growing interest in immune and inflammatory pathways as components of PTSD biology and comorbidity.
Co-principal investigator Murray B. Stein, MD, MPH, Distinguished Professor of Psychiatry and Family Medicine and Public Health, noted the importance of replication: the ANKRD55 association is biologically plausible given prior links to immune-related disease, but additional research is necessary to confirm and characterize this relationship. Co-principal investigator Robert J. Ursano, MD, emphasized that future studies should investigate how genetic risk interacts with trauma exposure, environment, and other biological processes to influence PTSD onset and course.
The study team included investigators from UC San Diego, Uniformed Services University, Harvard Medical School, Broad Institute, Yale University, University of Michigan, Harvard University, National Institutes of Mental Health, and other institutions. Key contributors named by the research group included Adam X. Maihofer, Caroline M. Nievergelt, Michael L. Thomas, Sonia Jain, Xiaoying Sun, Chia-Yen Chen, Jordan W. Smoller, Benjamin M. Neale, Stephan Ripke, Tianxi Cai, Joel Gelernter, Kevin P. Jensen, Renato Polimanti, Qian Wang, Steven G. Heeringa, Colter Mitchell, Erin B. Ware, Matthew K. Nock, Susan Borja, Ronald C. Kessler, and colleagues within the STARRS consortium.
Funding: The research received support from the Department of the Army, the U.S. Department of Health and Human Services, the National Institutes of Health, the National Institute of Mental Health, and the National Institute on Drug Abuse.
Abstract
Genome-wide Association Studies of Posttraumatic Stress Disorder in 2 Cohorts of US Army Soldiers
Importance: PTSD is a common and serious public health concern, particularly among military personnel. Identifying genetic risk factors may reveal biological pathways that underlie vulnerability and comorbidity with other conditions.
Objective: To discover genetic loci associated with lifetime PTSD risk in two cohorts from Army STARRS, using coordinated GWAS approaches and ancestry-specific analyses followed by meta-analysis.
Design, Setting, and Participants: The New Soldier Study enrolled 3,167 PTSD cases and 4,607 trauma-exposed controls; the Pre/Post Deployment Study enrolled 947 PTSD cases and 4,969 trauma-exposed controls. Data collection occurred during 2011–2012. Primary comparisons assessed DSM-IV lifetime PTSD versus trauma-exposed controls without PTSD.
Main Outcomes and Measures: Association analyses used logistic regression stratified by ancestry (European, African, Latino American) and study, with subsequent meta-analysis. The team estimated SNP-based heritability, genetic correlations, and pleiotropy with other psychiatric and immune-related disorders.
Results: A chromosome 5 locus in ANKRD55 reached genome-wide significance in African-American samples from the NSS and remained significant after adjusting for cumulative trauma exposure. A chromosome 19 locus near ZNF626 reached genome-wide significance in European-American NSS samples. These SNP associations were not replicated across both cohorts or in trans-ancestral analyses. SNP-based heritability estimates were nonsignificant. No consistent genetic correlations with six psychiatric or nine immune disorders were detected, but pleiotropy was observed between PTSD and rheumatoid arthritis, and to a lesser extent, psoriasis.
Conclusions and Relevance: This largest-to-date GWAS of PTSD in a U.S. military sample identified limited evidence for specific loci, including ANKRD55, which has prior links to autoimmune and inflammatory conditions. Replication and expanded studies are needed to confirm these signals and to clarify the genetic overlap between PTSD and immune-mediated disorders.