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Original Investigation |

Genome-wide Association Studies of Posttraumatic Stress Disorder in 2 Cohorts of US Army Soldiers

Murray B. Stein, MD, MPH1,2,3; Chia-Yen Chen, ScD4,5; Robert J. Ursano, MD6; Tianxi Cai, ScD7; Joel Gelernter, MD8,9,10; Steven G. Heeringa, PhD11; Sonia Jain, PhD2; Kevin P. Jensen, PhD8; Adam X. Maihofer, MS1; Colter Mitchell, PhD11; Caroline M. Nievergelt, PhD1; Matthew K. Nock, PhD12; Benjamin M. Neale, PhD5; Renato Polimanti, PhD8,9,10; Stephan Ripke, MD5; Xiaoying Sun, MS2; Michael L. Thomas, PhD1; Qian Wang, PhD8,9,10,13; Erin B. Ware, PhD11; Susan Borja, PhD14; Ronald C. Kessler, PhD15; Jordan W. Smoller, MD, ScD4,5 ; for the Army Study to Assess Risk and Resilience in Servicemembers (STARRS) Collaborators
[+] Author Affiliations
1Department of Psychiatry, University of California, San Diego (UCSD), La Jolla
2Department of Family Medicine and Public Health, UCSD, La Jolla
3Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, California
4Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston
5Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge
6Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Maryland
7Harvard T. H. Chan School of Public Health, Boston, Massachusetts
8Department of Psychiatry, Yale University, New Haven, Connecticut
9Department of Genetics, Yale University, New Haven, Connecticut
10Department of Neurobiology, Yale University, New Haven, Connecticut
11Institute for Social Research, University of Michigan, Ann Arbor
12Department of Psychology, Harvard University, Cambridge, Massachusetts
13currently with Department of Computational Biology and Bioinformatics, Graduate School of Arts and Sciences, Yale University, New Haven, Connecticut
14National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
15Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts
JAMA Psychiatry. 2016;73(7):695-704. doi:10.1001/jamapsychiatry.2016.0350.
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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 participants with PTSD and 4607 trauma-exposed control individuals; the Pre/Post Deployment Study (PPDS) included 947 unique participants 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.

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Figure 1.
Manhattan Plots of the New Soldier Study (NSS) Meta-analysis

A, The NSS meta-analysis of African American samples identifies a genome-wide significant association for posttraumatic stress disorder (PTSD) with rs159572 on chromosome 5. B, The NSS meta-analysis of European American samples identifies a genome-wide significant association for PTSD with rs11085374 on chromosome 19. Diamond indicates the single-nucleotide polymorphism with the lowest P value.

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Figure 2.
Meta-analysis for Single-Nucleotide Polymorphism rs159572 Between African American Samples

Different marker sizes indicate the precision of the odds ratio (OR) estimate for each study in the meta-analysis (larger means more precise). Army STARRS indicates Army Study to Assess Risk and Resilience in Servicemembers; NSS, New Soldier Study; and PPDS, Pre/Post Deployment Study.

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