Largest genome-wide association studies of PTSD to date identify two gene markers linked to military personnel who develop mental disorder.
In a massive analysis of DNA samples from more than 13,000 U.S. soldiers, scientists have identified two statistically significant genetic variants that may be associated with an increased risk of post-traumatic stress disorder (PTSD), an often serious mental illness linked to earlier exposure to a traumatic event, such as combat and an act of violence.
The U.S. Department of Veterans Affairs estimates 11 to 20 percent of veterans from the Afghanistan and Iraq conflicts have or will develop PTSD. The percentage is even higher among Vietnam War veterans. Prevalence of PTSD in the general U.S. population is 7 to 8 percent.
The findings, described by researchers at University of California San Diego School of Medicine, Veterans Affairs San Diego Healthcare System, the Uniformed Services University and colleagues elsewhere, are published online today in JAMA Psychiatry.
The study was designed to discover genetic loci associated with lifetime PTSD risk among U.S. Army personnel. Two coordinated, genome-wide association studies (GWAS) were conducted in two cohorts of consenting soldiers in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). A GWAS is a study that involves rapidly scanning markers across complete sets of DNA or genomes of many people to find genetic variants associated with a particular disease.
The first GWAS was performed on 3,167 diagnosed cases of PTSD and 4,607 trauma-exposed controls from the New Soldier Study; the second on 947 diagnosed cases and 4,969 trauma-exposed controls from the Pre/Post Deployment Study. The primary analysis compared lifetime PTSD cases, as defined by the Diagnostic Service Manual-IV, to trauma-exposed controls without lifetime PTSD.
“We found two notable genetic variants,” said co-principal investigator Murray B. Stein, MD, MPH, Distinguished Professor of Psychiatry and Family Medicine and Public Health at UC San Diego. “The first, in samples from African-American soldiers with PTSD, was in a gene (ANKRD55) on chromosome 5. In prior research, this gene has been found to be associated with various autoimmune and inflammatory disorders, including multiple sclerosis, type II diabetes, celiac disease, and rheumatoid arthritis. The other variant was found on chromosome 19 in European-American samples.”
There were no significant genetic correlations observed between PTSD and six mental disorders and nine immune-related disorders, said the study’s other co-principal investigator Robert J. Ursano, MD, professor and chair of the Department of Psychiatry at Uniformed Services University in Bethesda, Md. But there was significant evidence of pleiotropy — genetic factors that influence multiple traits — for PTSD and rheumatoid arthritis, and to a lesser extent, psoriasis.
“Further research will be needed to replicate the genome-wide significant association we found with the gene ANKRD55 and clarify the nature of the genetic overlap observed between PTSD and rheumatoid arthritis and psoriasis,” said Ursano.
About this genetics research
Co-authors of the study include: Adam X. Maihofer, Caroline M. Nievergelt, Michael L. Thomas, Sonia Jain, Xiaoying Sun, all at UC San Diego; Chia-Yen Chen, and Jordan W. Smoller, Massachusetts General Hospital and Harvard Medical School; Benjamin M. Neale, and Stephan Ripke, Broad Institute of Massachusetts Institute of Technology and Harvard; Tianxi Cai, Harvard T.H. Chan School of Public Health; Joel Gelernter, Kevin P. Jensen, Renato Polimanti, and Qian Wang, Yale University; Steven G. Heeringa, Colter Mitchell, and Erin B. Ware, University of Michigan; Matthew K. Nock, Harvard University; Susan Borja, National Institutes of Mental Health; and Ronald C. Kessler, Harvard Medical School.
Funding: Funding for this study came, in part, from the Department of the Army, the U.S. Department of Health and Human Services, the National Institutes of Health (UO1MH087981), the National Institute for Mental Health and the National Institute of Drug Abuse.
Source: Scott LaFee – UCSD Image Credit: The image is in the public domain. Original Research:Abstract for “Genome-wide Association Studies of Posttraumatic Stress Disorder in 2 Cohorts of US Army Soldiers” by Murray B. Stein, MD, MPH; Chia-Yen Chen, ScD; Robert J. Ursano, MD; Tianxi Cai, ScD; Joel Gelernter, MD; Steven G. Heeringa, PhD; Sonia Jain, PhD; Kevin P. Jensen, PhD; Adam X. Maihofer, MS; Colter Mitchell, PhD; Caroline M. Nievergelt, PhD; Matthew K. Nock, PhD; Benjamin M. Neale, PhD; Renato Polimanti, PhD; Stephan Ripke, MD; Xiaoying Sun, MS; Michael L. Thomas, PhD; Qian Wang, PhD; Erin B. Ware, PhD1; Susan Borja, PhD; Ronald C. Kessler, PhD; Jordan W. Smoller, MD, ScD; for the Army Study to Assess Risk and Resilience in Servicemembers (STARRS) Collaborators in JAMA Psychiatry. Published online May 11 2016 doi:10.1001/jamapsychiatry.2016.0350
Genome-wide Association Studies of Posttraumatic Stress Disorder in 2 Cohorts of US Army Soldiers
Importance Posttraumatic stress disorder (PTSD) is a prevalent, serious public health concern, particularly in the military. The identification of genetic risk factors for PTSD may provide important insights into the biological foundation of vulnerability and comorbidity.
Objective To discover genetic loci associated with the lifetime risk for PTSD in 2 cohorts from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS).
Design, Setting, and Participants Two coordinated genome-wide association studies of mental health in the US military contributed participants. The New Soldier Study (NSS) included 3167 unique patients with PTSD and 4607 trauma-exposed control individuals; the Pre/Post Deployment Study (PPDS) included 947 unique patients with PTSD and 4969 trauma-exposed controls. The NSS data were collected from February 1, 2011, to November 30, 2012; the PDDS data, from January 9 to April 30, 2012. The primary analysis compared lifetime DSM-IV PTSD cases with trauma-exposed controls without lifetime PTSD. Data were analyzed from March 18 to December 27, 2015.
Main Outcomes and Measures Association analyses for PTSD used logistic regression models within each of 3 ancestral groups (European, African, and Latino American) by study, followed by meta-analysis. Heritability and genetic correlation and pleiotropy with other psychiatric and immune-related disorders were estimated.
Results The NSS population was 80.7% male (6277 of 7774 participants; mean [SD] age, 20.9 [3.3] years); the PPDS population, 94.4% male (5583 of 5916 participants; mean [SD] age, 26.5 [6.0] years). A genome-wide significant locus was found in ANKRD55 on chromosome 5 (rs159572; odds ratio [OR], 1.62; 95% CI, 1.37-1.92; P = 2.34 × 10−8) and persisted after adjustment for cumulative trauma exposure (adjusted OR, 1.64; 95% CI, 1.39-1.95; P = 1.18 × 10−8) in the African American samples from the NSS. A genome-wide significant locus was also found in or near ZNF626 on chromosome 19 (rs11085374; OR, 0.77; 95% CI, 0.70-0.85; P = 4.59 × 10−8) in the European American samples from the NSS. Similar results were not found for either single-nucleotide polymorphism in the corresponding ancestry group from the PPDS sample, in other ancestral groups, or in transancestral meta-analyses. Single-nucleotide polymorphism–based heritability was nonsignificant, and no significant genetic correlations were observed between PTSD and 6 mental disorders or 9 immune-related disorders. Significant evidence of pleiotropy was observed between PTSD and rheumatoid arthritis and, to a lesser extent, psoriasis. Conclusions and Relevance In the largest genome-wide association study of PTSD to date, involving a US military sample, limited evidence of association for specific loci was found. Further efforts are needed to replicate the genome-wide significant association with ANKRD55—associated in prior research with several autoimmune and inflammatory disorders—and to clarify the nature of the genetic overlap observed between PTSD and rheumatoid arthritis and psoriasis.
“Genome-wide Association Studies of Posttraumatic Stress Disorder in 2 Cohorts of US Army Soldiers” by Murray B. Stein, MD, MPH; Chia-Yen Chen, ScD; Robert J. Ursano, MD; Tianxi Cai, ScD; Joel Gelernter, MD; Steven G. Heeringa, PhD; Sonia Jain, PhD; Kevin P. Jensen, PhD; Adam X. Maihofer, MS; Colter Mitchell, PhD; Caroline M. Nievergelt, PhD; Matthew K. Nock, PhD; Benjamin M. Neale, PhD; Renato Polimanti, PhD; Stephan Ripke, MD; Xiaoying Sun, MS; Michael L. Thomas, PhD; Qian Wang, PhD; Erin B. Ware, PhD1; Susan Borja, PhD; Ronald C. Kessler, PhD; Jordan W. Smoller, MD, ScD; for the Army Study to Assess Risk and Resilience in Servicemembers (STARRS) Collaborators in JAMA Psychiatry. Published online May 11 2016 doi:10.1001/jamapsychiatry.2016.0350