{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:12:29Z","timestamp":1790082749085,"version":"4.0.1"},"posted":{"date-parts":[[2026,9,17]]},"group-title":"Addiction Medicine","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01AA029758"],"award-info":[{"award-number":["R01AA029758"]}],"id":[{"id":"https:\/\/ror.org\/02jzrsm59","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  N\n                  <jats:sup>6<\/jats:sup>\n                  -methyladenosine (m\n                  <jats:sup>6<\/jats:sup>\n                  A) is the most abundant internal mRNA modification, dynamically regulating post-transcriptional gene expression. Although m\n                  <jats:sup>6<\/jats:sup>\n                  A dysregulation has been implicated in addiction neurobiology, comprehensive characterization of m\n                  <jats:sup>6<\/jats:sup>\n                  A alterations in alcohol use disorder (AUD) remains unexplored. We profiled m\n                  <jats:sup>6<\/jats:sup>\n                  A methylomes across eight reward- and motor-related brain regions in postmortem tissue from 12 AUD subjects and 12 matched controls (192 samples total) using MazF-mediated enzymatic cleavage and microarray-based m\n                  <jats:sup>6<\/jats:sup>\n                  A site mapping. Region-specific differential analysis identified 1,403 differentially methylated m\n                  <jats:sup>6<\/jats:sup>\n                  A sites (\n                  <jats:italic>P<\/jats:italic>\n                  &lt; 0.05, |fold change| \u2265 1.5): amygdala (n = 198), caudate nucleus (n = 91), cerebellum (n = 201), hippocampus (n = 89), nucleus accumbens (n = 276), prefrontal cortex (n = 362), putamen (n = 142), and ventral tegmental area (n = 241). Host transcripts were enriched for functional categories spanning intercellular communication, immune and inflammatory responses, RNA and protein synthesis, energy metabolism, and neurodegeneration. Gene set enrichment analysis revealed a coordinated inverse relationship between m\n                  <jats:sup>6<\/jats:sup>\n                  A methylation status and transcript abundance: hypermethylated transcripts were enriched among downregulated genes and hypomethylated transcripts among upregulated genes, consistent with m\n                  <jats:sup>6<\/jats:sup>\n                  A-mediated transcript destabilization. Cross-validation with Allen Human Brain Atlas region-specific expression profiles demonstrated that differential methylation patterns were primarily AUD-driven rather than secondary to regional transcriptional heterogeneity. These findings position m\n                  <jats:sup>6<\/jats:sup>\n                  A epitranscriptomics as a novel molecular signature of AUD and suggest that m\n                  <jats:sup>6<\/jats:sup>\n                  A regulatory machinery may serve as a therapeutic target. Future studies with larger validation cohorts and mechanistic interrogation are essential to establish causal relationships and facilitate translation to drug development.\n                <\/jats:p>","DOI":"10.64898\/2026.09.16.26363234","type":"posted-content","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:23:13Z","timestamp":1789708993000},"source":"Crossref","is-referenced-by-count":0,"title":["Altered m\n                  <sup>6<\/sup>\n                  A methylation across eight reward- and motor-related brain regions in alcohol use disorder"],"prefix":"10.64898","author":[{"given":"Abhishek","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"},{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ojong Tabi","family":"Ojong Besong","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"},{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhyuday Singh","family":"Parihar","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"},{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Sun","family":"Koo","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"},{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aravind","family":"Panicker","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"},{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohana","family":"Kefella","sequence":"additional","affiliation":[{"name":"Department of Medicine (Computational Biomedicine), Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Beane","sequence":"additional","affiliation":[{"name":"Department of Medicine (Computational Biomedicine), Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4902-0104","authenticated-orcid":false,"given":"Huiping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"},{"name":"Department of Medicine (Biomedical Genetics), Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092205350637000_2026.09.16.26363234v1.1","doi-asserted-by":"publisher","DOI":"10.1111\/adb.12855"},{"issue":"3","key":"2026092205350637000_2026.09.16.26363234v1.2","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1038\/s41380-021-01378-6","article-title":"Epigenome-wide association study of alcohol consumption in N = 8161 individuals and relevance to alcohol use disorder pathophysiology: identification of the cystine\/glutamate transporter SLC7A11 as a top target","volume":"27","year":"2022","journal-title":"Molecular psychiatry"},{"issue":"10","key":"2026092205350637000_2026.09.16.26363234v1.3","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1111\/acer.14168","article-title":"Epigenome-Wide DNA Methylation Association Analysis Identified Novel Loci in Peripheral Cells for Alcohol Consumption Among European American Male Veterans","volume":"43","year":"2019","journal-title":"Alcohol Clin Exp Res"},{"key":"2026092205350637000_2026.09.16.26363234v1.4","doi-asserted-by":"crossref","unstructured":"Wang F , Xu H , Zhao H , Gelernter J , Zhang H . 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