Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Sep;174(6):619-630.
doi: 10.1002/ajmg.b.32568. Epub 2017 Jul 10.

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

Andrew Ratanatharathorn  1 , Marco P Boks  2 , Adam X Maihofer  3 , Allison E Aiello  4 , Ananda B Amstadter  5 , Allison E Ashley-Koch  6 , Dewleen G Baker  3   7   8 , Jean C Beckham  9   10   11 , Evelyn Bromet  12 , Michelle Dennis  9   11 , Melanie E Garrett  6 , Elbert Geuze  2   13 , Guia Guffanti  14   15 , Michael A Hauser  6 , Varun Kilaru  16 , Nathan A Kimbrel  9   10   11 , Karestan C Koenen  17   18   19 , Pei-Fen Kuan  20 , Mark W Logue  21   22 , Benjamin J Luft  23 , Mark W Miller  22   24 , Colter Mitchell  25 , Nicole R Nugent  26 , Kerry J Ressler  14   15   27 , Bart P F Rutten  28 , Murray B Stein  3   7   29 , Eric Vermetten  2   30   31   32 , Christiaan H Vinkers  2 , Nagy A Youssef  33 ; VA Mid-Atlantic MIRECC Workgroup  9 ; PGC PTSD Epigenetics Workgroup; Monica Uddin  34   35 , Caroline M Nievergelt  3   7   8 , Alicia K Smith  16   27
Affiliations

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

Andrew Ratanatharathorn et al. Am J Med Genet B Neuropsychiatr Genet. 2017 Sep.

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.

Keywords: EWAS; meta-analysis; stress; trauma.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest

Dr. Youssef’s disclosures include Speaker CME honoraria from the Georgia Department of Behavioral Health and Developmental Disabilities (DHBDD). Dr. Youssef received research support from the Department of Veteran Affairs and The Augusta Biomedical Research Corporation. 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.

Figures

Figure 1
Figure 1
Sample size vs. power to to detect differentially methylated CpG sites. The black curve indicates the number of cases and controls necessary to find a differentially methylated if only one CpG site exists, while the gray line indicates the size necessary if 10 differentially methylated sites exist.
Figure 2
Figure 2
Ancestry inference using SNPs versus methylation probes in 128 participants of the Marine Resiliency Study (MRS). (a) Principal component (PC) plot showing ancestry inferred using SNPs from a genome-wide association study (GWAS). PC plots based on CpG probes with SNPs within 1 bp distance (b) and with SNPs within 10 bp distance (c), respectively. Subject are placed into four ancestral groups based on ancestry estimates using ancestry-informative SNPs and a reference panel (see methods).
Figure 3
Figure 3
PTSD genomic inflation factors (λ) by quality control pipeline (PGC vs. Funnorm) and standard error adjustment method (empirical Bayes vs. HC3).
See this image and copyright information in PMC

References

    1. Almli LM, Srivastava A, Fani N, Kerley K, Mercer KB, Feng H, Bradley B, Ressler KJ. Follow-up and Extension of a Prior Genome-wide Association Study of Posttraumatic Stress Disorder: Gene x Environment Associations and Structural Magnetic Resonance Imaging in a Highly Traumatized African-American Civilian Population. Biological psychiatry 2014 - PMC - PubMed
    1. Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, Irizarry RA. Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014:btu049. - PMC - PubMed
    1. Association AP. DSM-IV-TR: Diagnostic and statistical manual of mental disorders, text revision. Washington, DC: American Psychiatric Association; 2000. p. 75.
    1. Barfield RT, Almli LM, Kilaru V, Smith AK, Mercer KB, Duncan R, Klengel T, Mehta D, Binder EB, Epstein MP, Ressler KJ, Conneely KN. Accounting for population stratification in DNA methylation studies. Genetic epidemiology. 2014;38(3):231–241. - PMC - PubMed
    1. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B (Methodological) 1995:289–300.