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Accelerated epigenetic aging has been found in the blood and brain tissue of adults with DS but when premature aging in DS begins remains unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth. We assessed the association between age acceleration and DS using five epigenetic clocks in 346 newborns with DS and 567 newborns without DS using Illumina MethylationEPIC DNA methylation array data. We compared two epigenetic aging clocks (DNAmSkinBloodClock and pan\u2010tissue DNAmAge) and three epigenetic gestational age clocks (Haftorn, Knight, and Bohlin) between DS and non\u2010DS newborns using linear regression adjusting for observed age, sex, batch, deconvoluted blood cell proportions, and genetic ancestry. Targeted sequencing of <jats:italic>GATA1<\/jats:italic> was performed in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis. DS was significantly associated with increased DNAmSkinBloodClock (effect estimate\u00a0=\u00a00.2442, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), with an epigenetic age acceleration of 244\u2009days in newborns with DS after adjusting for potential confounding factors (95% confidence interval: 196\u2013292\u2009days). We also found evidence of epigenetic age acceleration associated with somatic <jats:italic>GATA1<\/jats:italic> mutations among newborns with DS (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.015). DS was not associated with epigenetic gestational age acceleration. We demonstrate that accelerated epigenetic aging in the blood of DS patients begins prenatally, with implications for the pathophysiology of immunosenescence and other aging\u2010related traits in DS.<\/jats:p>","DOI":"10.1111\/acel.13652","type":"journal-article","created":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T07:29:26Z","timestamp":1654500566000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Accelerated epigenetic aging in newborns with Down syndrome"],"prefix":"10.1111","volume":"21","author":[{"given":"Keren","family":"Xu","sequence":"first","affiliation":[{"name":"Center for Genetic Epidemiology, Department of Population and Public Health Sciences Keck School of Medicine of the University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0544-5338","authenticated-orcid":false,"given":"Shaobo","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology, Department of Population and Public Health Sciences Keck School of Medicine of the University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivo S.","family":"Muskens","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology, Department of Population and Public Health Sciences Keck School of Medicine of the University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalina","family":"Elliott","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swe Swe","family":"Myint","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology, Department of Population and Public Health Sciences Keck School of Medicine of the University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyatama","family":"Pandey","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology, Department of Population and Public Health Sciences Keck School of Medicine of the University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen M.","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libby M.","family":"Morimoto","sequence":"additional","affiliation":[{"name":"School of Public Health University of California, Berkeley  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice Y.","family":"Kang","sequence":"additional","affiliation":[{"name":"School of Public Health University of California, Berkeley  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Chronic Disease Epidemiology Yale School of Public Health  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Metayer","sequence":"additional","affiliation":[{"name":"School of Public Health University of California, Berkeley  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth A.","family":"Mueller","sequence":"additional","affiliation":[{"name":"Public Health Sciences Division, Fred Hutchinson Cancer Research Center, and Department of Epidemiology University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle\u00a0M.","family":"Walsh","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4110-3589","authenticated-orcid":false,"given":"Steve","family":"Horvath","sequence":"additional","affiliation":[{"name":"Department of Human Genetics David Geffen School of Medicine, University of California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph L.","family":"Wiemels","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology, Department of Population and Public Health Sciences Keck School of Medicine of the University of Southern California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4880-7543","authenticated-orcid":false,"given":"Adam J.","family":"de Smith","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology, Department of Population and Public Health Sciences Keck School of Medicine of the University of Southern California  Los Angeles California 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