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ASD is more commonly diagnosed in males, a disparity attributed to both biological sex differences and diagnostic biases. Identifying molecular biomarkers, such as DNA methylation signatures, could provide more objective screening for ASD-risk in newborns, allowing for early intervention. Epigenetic dysregulation has been reported in multiple tissues from newborns who are later diagnosed with ASD, but this is the first study to investigate sex-specific DNA methylation signatures for ASD in newborn blood, an accessible and widely banked tissue.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We assayed DNA methylation from newborn blood of ASD and typically developing (TD) individuals (discovery set\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009196, replication set\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200990) using whole genome bisulfite sequencing (WGBS). Sex-stratified differentially methylated regions (DMRs) were assessed for replication, comparisons by sex, overlaps with DMRs from other tissues, and enrichment for biological processes and SFARI ASD-risk genes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found that newborn blood ASD DMRs from both sexes significantly replicated in an independent cohort and were enriched for hypomethylation in ASD compared to TD samples, as well as location in promoters, CpG islands, and CpG island shores. By comparing female to male samples, we found that most sex-associated DMRs in TD individuals were also found in ASD individuals, alongside additional ASD-specific sex differences. Female-specific DMRs were enriched for X chromosomal location. Across both sexes, newborn blood DMRs overlapped significantly with DMRs from umbilical cord blood and placenta but not post-mortem cerebral cortex. DMRs from all tissues were enriched for neurodevelopmental processes (females) and known ASD genes (both sexes).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Overall, we identified and replicated a sex-specific DNA methylation signature of ASD in newborn blood that supported the female protective effect and highlighted convergence of epigenetic and genetic signatures of ASD in newborns. Despite the study\u2019s limitations, particularly in female sample sizes, our results demonstrate the potential of newborn blood in ASD screening and emphasize the importance of sex-stratification in future studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13293-025-00712-9","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T02:41:38Z","timestamp":1745980898000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Sex-specific DNA methylation signatures of autism spectrum disorder from whole genome bisulfite sequencing of newborn blood"],"prefix":"10.1186","volume":"16","author":[{"given":"Julia S.","family":"Mouat","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nickilou Y.","family":"Krigbaum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Hakam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Thrall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George E.","family":"Kuodza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Mellis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dag H.","family":"Yasui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piera M.","family":"Cirillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunin J.","family":"Ludena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca J.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele A.","family":"La Merrill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irva","family":"Hertz-Picciotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara A.","family":"Cohn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine M.","family":"LaSalle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"712_CR1","unstructured":"Diagnostic and statistical manual of mental disorders: DSM-5\u2122, 5th ed. 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