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

Murray B Stein¹, Chia-Yen Chen², Robert J Ursano³, Tianxi Cai⁴, Joel Gelernter⁵, Steven G Heeringa⁶, Sonia Jain⁷, Kevin P Jensen⁸, Adam X Maihofer⁹, Colter Mitchell⁶, Caroline M Nievergelt⁹, Matthew K Nock¹⁰, Benjamin M Neale¹¹, Renato Polimanti⁵, Stephan Ripke¹¹, Xiaoying Sun⁷, Michael L Thomas⁹, Qian Wang¹², Erin B Ware⁶, Susan Borja¹³, Ronald C Kessler¹⁴, Jordan W Smoller²; Army Study to Assess Risk and Resilience in Servicemembers (STARRS) Collaborators

Affiliations

¹ Department of Psychiatry, University of California, San Diego (UCSD), La Jolla2Department of Family Medicine and Public Health, UCSD, La Jolla3Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, California.
² Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston5Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge.
³ Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
⁴ Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
⁵ Department of Psychiatry, Yale University, New Haven, Connecticut9Department of Genetics, Yale University, New Haven, Connecticut10Department of Neurobiology, Yale University, New Haven, Connecticut.
⁶ Institute for Social Research, University of Michigan, Ann Arbor.
⁷ Department of Family Medicine and Public Health, UCSD, La Jolla.
⁸ Department of Psychiatry, Yale University, New Haven, Connecticut.
⁹ Department of Psychiatry, University of California, San Diego (UCSD), La Jolla.
¹⁰ Department of Psychology, Harvard University, Cambridge, Massachusetts.
¹¹ Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge.
¹² Department of Psychiatry, Yale University, New Haven, Connecticut9Department of Genetics, Yale University, New Haven, Connecticut10Department of Neurobiology, Yale University, New Haven, Connecticut13currently with Department of Computational Biology and.
¹³ National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
¹⁴ Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts.

PMID: 27167565
PMCID: PMC4936936
DOI: 10.1001/jamapsychiatry.2016.0350

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

Murray B Stein et al. JAMA Psychiatry. 2016.

. 2016 Jul 1;73(7):695-704.

doi: 10.1001/jamapsychiatry.2016.0350.

Authors

Affiliations

¹ Department of Psychiatry, University of California, San Diego (UCSD), La Jolla2Department of Family Medicine and Public Health, UCSD, La Jolla3Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, California.
² Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston5Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge.
³ Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
⁴ Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
⁵ Department of Psychiatry, Yale University, New Haven, Connecticut9Department of Genetics, Yale University, New Haven, Connecticut10Department of Neurobiology, Yale University, New Haven, Connecticut.
⁶ Institute for Social Research, University of Michigan, Ann Arbor.
⁷ Department of Family Medicine and Public Health, UCSD, La Jolla.
⁸ Department of Psychiatry, Yale University, New Haven, Connecticut.
⁹ Department of Psychiatry, University of California, San Diego (UCSD), La Jolla.
¹⁰ Department of Psychology, Harvard University, Cambridge, Massachusetts.
¹¹ Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge.
¹² Department of Psychiatry, Yale University, New Haven, Connecticut9Department of Genetics, Yale University, New Haven, Connecticut10Department of Neurobiology, Yale University, New Haven, Connecticut13currently with Department of Computational Biology and.
¹³ National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
¹⁴ Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts.

PMID: 27167565
PMCID: PMC4936936
DOI: 10.1001/jamapsychiatry.2016.0350

Abstract

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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Figures

**Figure 1**
Manhattan plots of NSS1 and NSS2 meta-analysis in European American and African American samples (a). NSS meta-analysis, African American samples, identifying genome-wide significant association for PTSD with rs159572 on Chr 5 (b). NSS meta-analysis, European American samples, identifying a genome-wide significant association for PTSD with rs11085374 on Chr 19

**Figure 2**
Meta-analysis for SNP rs159572 between African American samples from Army STARRS, Marine Resiliency Study and Ashley-Koch et al. 2015

See this image and copyright information in PMC

References

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

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

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