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Author Notes:

Correspondence: Alicia K. Smith, Ph.D., Emory University School of Medicine, 101 Woodruff Circle NE, Ste 4217, Atlanta, GA 30322. Phone: 404-712-5006. Email: alicia.smith@emory.edu.

See publication for full list of authors.

Acknowledgments: Acknowledged are Victoria B. Risbrough Ph.D (VA San Diego Healthcare System & UCSD), Mark A. Geyer (UCSD), Daniel T. O’Connor (UCSD), all MRS investigators, and all MRS investigators, as well as the MRS administrative core and data collection staff listed in the Methods article (Baker et al, Prev Chronic Dis. 2012;9(10):E97).

The authors also thank the Marine and Navy Corpsmen volunteers for military service and participation in MRS.

This research is the result of work supported with resources and the use of facilities at the Pharmacogenomics Analysis Laboratory, Research and Development Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas.

Disclosures: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the VA, NIH, or the United States government.

Dr. Youssef’s disclosures include Speaker CME honoraria from the Georgia Department of Behavioral Health and Developmental Disabilities (DHBDD).

Dr. Stein has in the past 3 years received payments for editorial work from UpToDate, Biological Psychiatry, and Depression and Anxiety. He has also in the past 3 years been paid as a consultant for Actelion Pharmaceuticals, Janssen, Pfizer, Resilience Therapeutics, and Tonix Pharmaceuticals.

No other author declares any conflict of interest.

Subjects:

Research Funding:

This work was supported by the U.S. Army Medical Research and Materiel Command and the National Institute of Mental Health (NIMH; R01MH108826) as well as the Biomedical and Laboratory Research and Development (#I01BX002577).

We appreciate the technical support of all of the staff, volunteers and participants from the Grady Trauma Project, supported by the National Institutes of Mental Health (MH096764 and MH071537).

DNHS, which is grateful to all of the participants and staff for their contributions, was funded by NIH Awards R01DA022720, R01DA022720-S1, and RC1MH088283.

The Marine Corps, Navy Bureau of Medicine and Surgery (BUMED) and VA Health Research and Development (HSR&D) provided funding for MRS data collection and analysis and NIH R01MH093500 funded the GWAS assays and analysis.

Data collection of PRISMO was funded by the Dutch Ministry of Defence, and DNA methylation analyses were funded by the VENI Award fellowship from the Netherlands Organisation for Scientific Research (NWO, grant number 916.11.086).

The VA Boston-National Center for PTSD Study research was supported in part by National Institute of Mental Health Award RO1MH079806, Department of Veterans Affairs, Clinical Science Research & Development Program Award 5I01CX000431-02, Department of Veterans Affairs, Biomedical Laboratory Research & Development Program Award 1I01BX002150-01, the Translational Research Center for TBI and Stress Disorders (TRACTS), a VA Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (B9254-C), and the Cooperative Studies Program, Department of Veterans Affairs.

This work was also supported by a Career Development Award to E. J. Wolf from the Department of Veterans Affairs, Clinical Sciences Research, and Development Program.

Dr. Kimbrel was supported by a Career Development Award (#IK2CX000525) from the Clinical Science Research and Development (CSR&D).

Dr. Beckham was supported by a Research Career Scientist Award (#11S-RCS-009) from the CSR&D Service of VA ORD.

This research was also supported, in part, by a Merit Award (#I01BX002577) from the Biomedical Laboratory Research and Development (BLR&D) Service of VA ORD.

Data collection from the World Trade Center (WTC) cohort was supported by CDC awards U01OH010416, U01OH010718, and 200-2011-39410.

Dr. Youssef received research support from the Department of Veteran Affairs and The Augusta Biomedical Research Corporation.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • Psychiatry
  • EWAS
  • meta-analysis
  • stress
  • trauma
  • POSTTRAUMATIC-STRESS-DISORDER
  • FALSE DISCOVERY RATE
  • NATIONAL COMORBIDITY SURVEY
  • INDIVIDUAL PATIENT DATA
  • CORONARY-HEART-DISEASE
  • DNA METHYLATION
  • GLUCOCORTICOID-RECEPTOR
  • ENVIRONMENTAL-INFLUENCES
  • SAMPLE-SIZE
  • TRAUMA

Epigenome-wide association of PTSD from heterogeneous cohorts with a common multi-site analysis pipeline

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Journal Title:

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

Volume:

Volume 174, Number 6

Publisher:

, Pages 619-630

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Compelling evidence suggests that epigenetic mechanisms such as DNA methylation play a role in stress regulation and in the etiologic basis of stress related disorders such as Post traumatic Stress Disorder (PTSD). Here we describe the purpose and methods of an international consortium that was developed to study the role of epigenetics in PTSD. Inspired by the approach used in the Psychiatric Genomics Consortium, we brought together investigators representing seven cohorts with a collective sample size of N = 1147 that included detailed information on trauma exposure, PTSD symptoms, and genome-wide DNA methylation data. The objective of this consortium is to increase the analytical sample size by pooling data and combining expertise so that DNA methylation patterns associated with PTSD can be identified. Several quality control and analytical pipelines were evaluated for their control of genomic inflation and technical artifacts with a joint analysis procedure established to derive comparable data over the cohorts for meta-analysis. We propose methods to deal with ancestry population stratification and type I error inflation and discuss the advantages and disadvantages of applying robust error estimates. To evaluate our pipeline, we report results from an epigenome-wide association study (EWAS) of age, which is a well-characterized phenotype with known epigenetic associations. Overall, while EWAS are highly complex and subject to similar challenges as genome-wide association studies (GWAS), we demonstrate that an epigenetic meta-analysis with a relatively modest sample size can be well-powered to identify epigenetic associations. Our pipeline can be used as a framework for consortium efforts for EWAS.

Copyright information:

© 2017 Wiley Periodicals, Inc.

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