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Abstract：
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.
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.
摘要：
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,该队列使用IlluminaEPIC甲基化BeadChip评估基因组中超过850,000个位点的DNAm.我们的模型包括祖先的协变量，细胞异质性，性别,年龄,和基于DNAm的39个吸烟相关CpG的吸烟评分。我们还检查了来自国家PTSD脑库（n=72）的前额叶皮质（PFC）组织产生的基于EPIC的DNAm数据。
对血液样本的分析在基因G0S2的cg19534438处产生了与PTSD的全基因组显著关联(p=1.19×10-7,padj=0.048)。这种关联在军事队列的独立PGC-PTSD-EWAS联盟荟萃分析中得到了复制（p=0.0024）。尽管包含基于甲基化的吸烟评分协变量（p=9.16×10-6），我们还观察到与AHRR中吸烟相关的基因座cg05575921的关联。它复制了先前观察到的PGC-PTSD-EWAS关联(Smith等人。2019),并产生与吸烟无关效应一致的证据。然后在PFC数据中检查前100个EWAS基因座。基于血液的创伤后应激障碍基因座之一，CHST11中的cg04130728，在血液中排名前10位，但这对全基因组来说并不重要，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，效果方向相同）。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显著重叠的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某些PTSD关联可能反映了大脑中的关联。
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,该队列使用IlluminaEPIC甲基化BeadChip评估基因组中超过850,000个位点的DNAm.我们的模型包括祖先的协变量，细胞异质性，性别,年龄,和基于DNAm的39个吸烟相关CpG的吸烟评分。我们还检查了来自国家PTSD脑库（n=72）的前额叶皮质（PFC）组织产生的基于EPIC的DNAm数据。
对血液样本的分析在基因G0S2的cg19534438处产生了与PTSD的全基因组显著关联(p=1.19×10-7,padj=0.048)。这种关联在军事队列的独立PGC-PTSD-EWAS联盟荟萃分析中得到了复制（p=0.0024）。尽管包含基于甲基化的吸烟评分协变量（p=9.16×10-6），我们还观察到与AHRR中吸烟相关的基因座cg05575921的关联。它复制了先前观察到的PGC-PTSD-EWAS关联(Smith等人。2019),并产生与吸烟无关效应一致的证据。然后在PFC数据中检查前100个EWAS基因座。基于血液的创伤后应激障碍基因座之一，CHST11中的cg04130728，在血液中排名前10位，但这对全基因组来说并不重要，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，效果方向相同）。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显著重叠的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某些PTSD关联可能反映了大脑中的关联。
