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Am J Med Genet B Neuropsychiatr Genet. 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.

Author information

1
Department of Epidemiology, Columbia University, New York, New York.
2
Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands.
3
Department of Psychiatry, University of California San Diego, San Diego, California.
4
Department of Epidemiology, UNC Chapel Hill, Chapel Hill, North Carolina.
5
Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia.
6
Duke Molecular Physiology Institute, Durham, North Carolina.
7
Veterans Affairs San Diego Healthcare System, San Diego, California.
8
Veterans Affairs Center of Excellence for Stress and Mental Health, San Diego, California.
9
Mental Illness Research, Education, and Clinical Center, VA Mid-Atlantic, Durham, North Carolina.
10
Durham VA Medical Center, Durham, North Carolina.
11
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.
12
Epidemiology Research Group, State University of New York, New York.
13
Military Mental Healthcare-Research Centre, Ministry of Defence, Utrecht, Netherlands.
14
Neurobiology of Fear Laboratory, McLean Hospital, Belmont, Massachusetts.
15
Department of Epidemiology and Massachusetts General Hospital, Department of Psychiatry, Harvard T.H. Chan School of Public Health, Belmont, Massachusetts.
16
Department of Gynecology and Obstetrics, Emory University, Atlanta, Georgia.
17
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
18
Center for Human Genetic Research, and Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.
19
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
20
Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York.
21
Department of Medicine (Biomedical Genetics), Boston University, Boston, Massachusetts.
22
VA Boston Healthcare System, Boston, Massachusetts.
23
Department of Medicine, State University of New York, New York.
24
Department of Psychiatry, Boston University School of Medicine,, Boston, Massachusetts.
25
Institute for Social Research, University of Michigan, Ann Arbor, Michigan.
26
Department of Pediatric Research, Psychiatry and Human Behavior, Brown University, Providence, Rhode Island.
27
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia.
28
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht,, Limburg, Netherlands.
29
Department of Family Medicine and Public Health, University of California San Diego, San Diego, California.
30
Department of Psychiatry, Leiden University Medical Center, Utrecht, Netherlands.
31
Military Mental Healthcare, Ministry of Defence, Utrecht, Netherlands.
32
Arq Psychotrauma Expert Group, Diemen, Netherlands.
33
Department of Psychiatry and Human Behavior and Office of Academic Affairs, Medical College of Georgia at Augusta University, Augusta, Georgia.
34
Department of Psychology, University of Illinois Urbana-Champaign, Urbana, Illinois.
35
Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, Illinois.

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

PMID:
28691784
PMCID:
PMC5592721
DOI:
10.1002/ajmg.b.32568
[Indexed for MEDLINE]
Free PMC Article

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