An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci.,Clinical Epigenetics

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An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci.
Clinical Epigenetics ( IF 5.7 ) Pub Date : 2020-03-14 , DOI: 10.1186/s13148-020-0820-0
Mark W Logue _{1,

2,

3,

4} , Mark W Miller _{1,

2} , Erika J Wolf _{1,

2} , Bertrand Russ Huber _{1,

2} , Filomene G Morrison _{1,

2} , Zhenwei Zhou ₄ , Yuanchao Zheng ₄ , Alicia K Smith _{5,

6} , Nikolaos P Daskalakis _{7,

8,

9,

10} , Andrew Ratanatharathorn ₁₁ , Monica Uddin _{12,

13} , Caroline M Nievergelt _{14,

15,

16} , Allison E Ashley-Koch ₁₇ , Dewleen G Baker _{14,

15,

18} , Jean C Beckham _{19,

20,

21} , Melanie E Garrett ₁₇ , Marco P Boks ₂₂ , Elbert Geuze _{22,

23} , Gerald A Grant ₂₄ , Michael A Hauser ₁₇ , Ronald C Kessler ₂₅ , Nathan A Kimbrel _{20,

21,

26} , Adam X Maihofer _{14,

15,

16} , Christine E Marx _{27,

28} , Xue-Jun Qin ₁₇ , Victoria B Risbrough _{14,

15,

16} , Bart P F Rutten ₂₉ , Murray B Stein _{14,

18,

30} , Robert J Ursano ₃₁ , Eric Vermetten _{32,

33,

34,

35} , Christiaan H Vinkers _{36,

37} , Erin B Ware ₃₈ , Annjanette Stone ₃₉ , Steven A Schichman ₃₉ , Regina E McGlinchey _{7,

40} , William P Milberg _{7,

40} , Jasmeet P Hayes _{1,

2,

41} , Mieke Verfaellie _{2,

42} ,

Affiliation

National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.
Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
,Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA.
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Department of Gynecology and Obstetrics, Emory University, Atlanta, GA, USA.
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
McLean Hospital, Belmont, MA, USA.
Cohen Veterans Bioscience, Cambridge, MA, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Epidemiology, Columbia University, New York, NY, USA.
Genomics Program, University of South Florida College of Public Health, Tampa, FL, USA.
,Global Health and Infectious Disease Research Program, University of South Florida College of Public Health, Tampa, FL, USA.
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.
Research, Durham VA Medical Center, Durham, NC, USA.
Genetics Research Laboratory, VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC), Durham, NC, USA.
Department of Psychiatry, UMC Utrecht Brain Center, Utrecht, Utrecht, Netherlands.
Brain Research and Innovation Centre, Netherlands Ministry of Defence, Utrecht, Utrecht, Netherlands.
Department of Neurosurgery, Stanford University Medical Center, Stanford, CA, USA.
Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
Department of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Psychiatry & Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht Universitair Medisch Centrum, Maastricht, Limburg, Netherlands.
Million Veteran Program, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
Department of Psychiatry, Uniformed Services University, Bethesda, MD, USA.
Arq, Psychotrauma Reseach Expert Group, Diemen, NH, Netherlands.
Department of Psychiatry, Leiden University Medical Center, Leiden, ZH, Netherlands.
Netherlands Defense Department, Research Center, Utrecht, UT, Netherlands.
Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
Department of Anatomy and Neurosciences, Amsterdam UMC (location VUmc), Amsterdam, Holland, Netherlands.
Department of Psychiatry, Amsterdam UMC (location VUmc), Amsterdam, Holland, Netherlands.
Institute for Social Research, Survey Research Center, University of Michigan, Michigan, MI, USA.
Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
Geriatric Research Educational and Clinical Center and Translational Research Center for TBI and Stress Disorders, VA Boston Health Care System, Boston, MA, USA.
Department of Psychology and Chronic Brain Injury Program, The Ohio State University, Columbus, OH, USA.
Memory Disorders Research Center, VA Boston Healthcare System and Boston University School of Medicine, Boston, MA, USA.

Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD). In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72). The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10-7, padj = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 × 10-6), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 × 10-5, padj = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including “Response to lipopolysaccharide” (p = 6.97 × 10-6, padj = 0.042). The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.

中文翻译：

美国退伍军人创伤后应激障碍的表观基因组关联研究涉及几个新的 DNA 甲基化位点。

先前使用候选基因和全基因组方法的研究已经确定了与创伤后应激障碍 (PTSD) 相关的 DNA 甲基化 (DNAm) 的表观遗传变化。在这项研究中，我们对来自 TBI 和应激障碍转化研究中心 (TRACTS) 队列的退伍军人队列（n = 378 例终生 PTSD 病例和 135 例对照）进行了 PTSD 的 EWAS，使用评估 DNAm 的 Illumina EPIC 甲基化 BeadChip 进行评估在整个基因组的超过 850,000 个位点。我们的模型包括血统、细胞异质性、性别、年龄和基于 39 个吸烟相关 CpG 的 DNAm 的吸烟评分的协变量。我们还检查了从国家 PTSD 脑库 (n = 72) 的前额皮质 (PFC) 组织生成的基于 EPIC 的 DNAm 数据。血液样本分析在基因 G0S2 的 cg19534438 处产生了一个与 PTSD 的全基因组显着关联（p = 1.19 × 10-7，padj = 0.048）。该关联在军事队列的独立 PGC-PTSD-EWAS 联合荟萃分析中得到复制 (p = 0.0024)。我们还观察到与 AHRR 中吸烟相关位点 cg05575921 的关联，尽管包含基于甲基化的吸烟评分协变量 (p = 9.16 × 10-6)，它复制了之前观察到的 PGC-PTSD-EWAS 关联（Smith 等人，2019 年） ), 并产生与吸烟独立效应一致的证据。然后在 PFC 数据中检查前 100 个 EWAS 位点。基于血液的 PTSD 位点之一，CHST11 中的 cg04130728，位于血液中的前 10 个位点中，但在全基因组范围内不显着，与脑组织中的 PTSD 显着相关（在血液中 p = 1. 19 × 10-5，padj = 0.60，在大脑中，p = 0.00032，作用方向相同）。前 500 个 EWAS 基因座的基因集富集分析产生了几个与病原体反应有关的重要重叠 GO 术语，包括“对脂多糖的反应”（p = 6.97 × 10-6，padj = 0.042）。在独立队列中观察到的交叉复制证明外周组织中的 DNA 甲基化可以产生一致且可复制的 PTSD 关联，我们的结果还表明，在外周组织中观察到的一些 PTSD 关联可能反映大脑中的关联。padj = 0.042）。在独立队列中观察到的交叉复制证明外周组织中的 DNA 甲基化可以产生一致且可复制的 PTSD 关联，我们的结果还表明，在外周组织中观察到的一些 PTSD 关联可能反映大脑中的关联。padj = 0.042）。在独立队列中观察到的交叉复制证明外周组织中的 DNA 甲基化可以产生一致且可复制的 PTSD 关联，我们的结果还表明，在外周组织中观察到的一些 PTSD 关联可能反映大脑中的关联。

更新日期：2020-04-22

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