{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T11:12:40Z","timestamp":1767006760853,"version":"build-2065373602"},"reference-count":46,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T00:00:00Z","timestamp":1762560000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["NI13332\/13-1","TRR265"],"award-info":[{"award-number":["NI13332\/13-1","TRR265"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"German Federal Ministry of Education and Research","award":["01ZX01909"],"award-info":[{"award-number":["01ZX01909"]}]},{"name":"BMBF-funded SysMedSUDs consortium","award":["01ZX1909A"],"award-info":[{"award-number":["01ZX1909A"]}]},{"name":"Hetzler Foundation for Addiction Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alcohol use disorder (AUD) is associated with widespread epigenetic alterations, including changes in DNA methylation (DNAm). This multi-cohort study validated and extended previous findings on DNAm of HECW2 and GDAP1 in AUD, assessed sex differences, and explored DNAm in blood and brain tissue in humans and rats. DNAm was measured via pyrosequencing in human blood (NCtrl = 341, NAUD = 258), postmortem frontal cortex (Brodmann area 9; discovery cohort: NCtrl = 10, NAUD = 13, replication cohort: NCtrl = 64, NAUD = 55) and rat blood and medial prefrontal cortex (NCtrl = 16, NAUD = 15). Gene expression was assessed in human postmortem brain by quantitative real-time PCR. AUD-associated DNAm differences in HECW2 and GDAP1 were replicated in human blood. While decreased GDAP1 DNAm was only observed in men, HECW2 hypomethylation was present in both sexes. In brain tissue, initial DNAm increases in AUD and HECW2 gene expression decreases were not validated in the replication cohort. In rats, HECW2 hypomethylation appeared in the prelimbic cortex but not in blood. Our findings support the involvement of HECW2 and GDAP1 DNAm in AUD, revealing sex-specific and tissue-dependent epigenetic patterns. The opposing DNAm directionality in blood and brain underscores the complexity of alcohol-related epigenetic modifications and suggests the need for multi-tissue, cross-species, and longitudinal studies to clarify causal mechanisms.<\/jats:p>","DOI":"10.3390\/ijms262210840","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T08:57:55Z","timestamp":1762765075000},"page":"10840","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Validation of GDAP1 and HECW2 as Epigenetic Markers of Alcohol Use Disorder in Blood and Brain"],"prefix":"10.3390","volume":"26","author":[{"given":"Ariane","family":"Wiegand","sequence":"first","affiliation":[{"name":"Max Planck Institute of Psychiatry, 80804 Munich, Germany"},{"name":"Department of Psychiatry and Psychotherapy, Tuebingen Center for Mental Health (T\u00fcCMH), University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany"},{"name":"German Center for Mental Health, Partner Site Munich-Augsburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3334-2555","authenticated-orcid":false,"given":"Marion","family":"Friske","sequence":"additional","affiliation":[{"name":"Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany"},{"name":"Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Edelmann","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Tuebingen Center for Mental Health (T\u00fcCMH), University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany"},{"name":"German Center for Mental Health (DZPG), Partner Site Tuebingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annika","family":"Bender","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Tuebingen Center for Mental Health (T\u00fcCMH), University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany"},{"name":"German Center for Mental Health (DZPG), Partner Site Tuebingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6764-2766","authenticated-orcid":false,"given":"Lea","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Tuebingen Center for Mental Health (T\u00fcCMH), University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany"},{"name":"Graduate School of Cellular and Molecular Neuroscience, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany"},{"name":"Institute of Human Genetics, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Zill","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, University Hospital, Ludwig Maximilian University, 80336 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Koller","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, University Hospital, Ludwig Maximilian University, 80336 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georgy","family":"Bakalkin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences, Uppsala University, SE-752 37 Uppsala, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang H.","family":"Sommer","sequence":"additional","affiliation":[{"name":"Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany"},{"name":"Bethania Hospital for Psychiatry, Psychosomatics and Psychotherapy, 17489 Greifswald, Germany"},{"name":"German Center for Mental Health (DZPG), Partner Site Mannheim-Heidelberg-Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita C.","family":"Hansson","sequence":"additional","affiliation":[{"name":"Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany"},{"name":"German Center for Mental Health (DZPG), Partner Site Mannheim-Heidelberg-Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7884-4500","authenticated-orcid":false,"given":"Vanessa","family":"Nieratschker","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Tuebingen Center for Mental Health (T\u00fcCMH), University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany"},{"name":"German Center for Mental Health (DZPG), Partner Site Tuebingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,8]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2024). 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