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Epigenetic mechanisms have been implicated in the etiology of PTSD, with DNA methylation being the most studied to identify novel molecular biomarkers associated with this disorder. We performed one of the largest single-sample epigenome-wide association studies (EWAS) of PTSD to date. Our sample included 1135 male European\u2013American U.S. veterans who participated in the National Health and Resilience in Veterans Study (NHRVS). DNA was collected from saliva samples and the Illumina HumanMethylation EPIC BeadChip was used for the methylation analysis. PTSD was assessed using the PTSD Checklist. An EWAS was conducted using linear regression adjusted for age, cell-type proportions, first 10 principal components, and smoking status. After Bonferroni correction, we identified six genome-wide significant (GWS) CpG sites associated with past-month PTSD and three CpGs with lifetime PTSD (<jats:italic>p<\/jats:italic><jats:sub>range<\/jats:sub>\u2009=\u200910<jats:sup>\u221210<\/jats:sup>\u201310<jats:sup>\u22128<\/jats:sup>). These CpG sites map to genes involved in immune function, transcription regulation, axonal guidance, cell signaling, and protein binding. Among these, <jats:italic>SENP7<\/jats:italic>, which is involved in transcription regulation and has been linked to risk-taking behavior and alcohol consumption in genome-wide association studies, replicated in an independent veteran cohort and was downregulated in medial orbitofrontal cortex of PTSD postmortem brain tissue. These findings suggest potential epigenetic biomarkers of PTSD that may help inform the pathophysiology of this disorder in veterans and other trauma-affected populations.<\/jats:p>","DOI":"10.1038\/s41398-022-01822-3","type":"journal-article","created":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T11:03:18Z","timestamp":1645095798000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Epigenome-wide association study of posttraumatic stress disorder identifies novel loci in U.S. military veterans"],"prefix":"10.1038","volume":"12","author":[{"given":"Janitza L.","family":"Montalvo-Ortiz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4067-1859","authenticated-orcid":false,"given":"Joel","family":"Gelernter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhongshan","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1647-326X","authenticated-orcid":false,"given":"Matthew J.","family":"Girgenti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6472-7052","authenticated-orcid":false,"given":"Ke","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8154-9334","authenticated-orcid":false,"given":"Xinyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2608-8472","authenticated-orcid":false,"given":"Shyamalika","family":"Gopalan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7694-6391","authenticated-orcid":false,"given":"Hang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8690-8439","authenticated-orcid":false,"given":"Ronald S.","family":"Duman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven M.","family":"Southwick","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6952-1726","authenticated-orcid":false,"given":"John H.","family":"Krystal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Traumatic Stress Brain Research Study Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew J.","family":"Friedman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald S.","family":"Duman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew J.","family":"Girgenti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John H.","family":"Krystal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janitza L.","family":"Montalvo-Ortiz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert H.","family":"Pietrzak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,2,17]]},"reference":[{"key":"1822_CR1","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.jpsychires.2016.06.022","volume":"82","author":"SM Smith","year":"2016","unstructured":"Smith SM, Goldstein RB, Grant BF. 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Consulting; Otsuka America Pharmaceutical, Inc.; Spring Care, Inc.; Sunovion Pharmaceuticals, Inc.; Takeda Industries; Taisho Pharmaceutical Co., Ltd; Scientific Advisory Board; Bioasis Technologies, Inc.; Biohaven Pharmaceuticals; Blackthorn Therapeutics, Inc.; Broad Institute of MIT and Harvard; Cadent Therapeutics; Lohocla Research Corporation; Pfizer Pharmaceuticals; Stanley Center for Psychiatric Research at the Broad Institute; (2) Stock: ArRETT Neuroscience, Inc.; Blackthorn Therapeutics, Inc.; Biohaven Pharmaceuticals Medical Sciences; Spring Care, Inc. Stock Options: Biohaven PharmaceuticalsMedical Sciences; (3) Income Greater than $10,000: Editorial BoardEditor\u2014Biological Psychiatry; Patents and Inventions: Seibyl JP, Krystal JH, Charney DS. Dopamine and noradrenergic reuptake inhibitors in the treatment of schizophrenia. US Patent #:5,447,948. September 5, 1995; Vladimir, Coric, Krystal, John H, Sanacora, Gerard\u2014Glutamate Modulating Agents in the Treatment of Mental Disorders US Patent No. 8,778,979 B2 Patent Issue Date: July 15, 2014. US Patent Application No. 15\/695,164: Filing Date: 09\/05\/2017; Charney D, Krystal JH, Manji H, Matthew S, Zarate C., Intranasal Administration of Ketamine to Treat Depression United States Application No. 14\/197,767 filed on March 5, 2014; United States application or Patent Cooperation Treaty (PCT) International application No. 14\/306,382 filed on June 17, 2014; Zarate, C, Charney, DS, Manji, HK, Mathew, Sanjay J, Krystal, JH, Department of Veterans Affairs \u201cMethods for Treating Suicidal Ideation\u201d, Patent Application No. 14\/197.767 filed on March 5, 2014 by Yale University Office of Cooperative Research; Arias A, Petrakis I, Krystal JH. Composition and methods to treat addiction; Provisional Use Patent Application no.61\/973\/961. April 2, 2014. Filed by Yale University Office of Cooperative Research; Chekroud, A., Gueorguieva, R., & Krystal, JH. \u201cTreatment Selection for Major Depressive Disorder\u201d [filing date 3rd June 2016, USPTO docket number Y0087.70116US00]. Provisional patent submission by Yale University; Yoon G, Petrakis I, Krystal JH. Compounds, Compositions, and Methods for Treating or Preventing Depression and Other Diseases. U. S. Provisional Patent Application No. 62\/444,552, filed on January10, 2017 by Yale University Office of Cooperative Research OCR 7088 US01; Abdallah, C, Krystal, JH, Duman, R, Sanacora, G. Combination Therapy for Treating or Preventing Depression or Other Mood Diseases. U.S. Provisional Patent Application No. 047162-7177P1 (00754) filed on August 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01. JG is named as an inventor on PCT patent application #15\/878,640 entitled: \u201cGenotype-guided dosing of opioid agonists,\u201d filed January 24, 2018. Other co-authors declare no completing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"65"}}