Epigenome-wide association of PTSD from heterogeneous cohorts with a common multi-site analysis pipeline.
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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. |
Year of Publication | 2017
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Journal | Am J Med Genet B Neuropsychiatr Genet
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Volume | 174
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Issue | 6
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Pages | 619-630
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Date Published | 2017 Sep
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ISSN | 1552-485X
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DOI | 10.1002/ajmg.b.32568
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PubMed ID | 28691784
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PubMed Central ID | PMC5592721
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Grant list | IK6 BX003777 / BX / BLRD VA / United States
R56 MH071537 / MH / NIMH NIH HHS / United States
R01 DA022720 / DA / NIDA NIH HHS / United States
R21 HD088931 / HD / NICHD NIH HHS / United States
R01 MH071537 / MH / NIMH NIH HHS / United States
U01 OH010718 / OH / NIOSH CDC HHS / United States
R21 MH112956 / MH / NIMH NIH HHS / United States
R01 AI129788 / AI / NIAID NIH HHS / United States
R01 MH096764 / MH / NIMH NIH HHS / United States
RC1 MH088283 / MH / NIMH NIH HHS / United States
R01 MH093500 / MH / NIMH NIH HHS / United States
I01 BX002577 / BX / BLRD VA / United States
I01 BX002150 / BX / BLRD VA / United States
U01 MH109536 / MH / NIMH NIH HHS / United States
U01 MH109514 / MH / NIMH NIH HHS / United States
I01 CX000431 / CX / CSRD VA / United States
R01 MH106595 / MH / NIMH NIH HHS / United States
R01 MH108826 / MH / NIMH NIH HHS / United States
P2C HD050924 / HD / NICHD NIH HHS / United States
IK2 CX000525 / CX / CSRD VA / United States
U01 OH010416 / OH / NIOSH CDC HHS / United States
R01 MH079806 / MH / NIMH NIH HHS / United States
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