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Chronic alcohol exposure is associated with alterations in both innate and adaptive immune cell populations that in turn contribute to AUD susceptibility and severity, suggesting a bidirectional gene-environment relationship. Yet, most clinical AUD studies of this system have relied on indirect measurement of immune function and\/or assessment of only a small number of cell types or immune markers, approaches which cannot capture the immune system\u2019s inherent complexity and cellular heterogeneity. Therefore, in order to better characterize immune dysregulation in AUD, the goal of this study was to use single cell RNA sequencing (scRNA-seq) in peripheral blood mononuclear cells (PBMCs) to compare immune cell proportions and differential gene expression between individuals with AUD and healthy controls. Our findings highlight a distinct disproportionality of lymphocytes and monocytes in individuals with AUD and healthy controls as well as sex and dose-dependent alterations immune cell functional characteristics. These peripheral blood cell-type proportions and dose-dependent signatures of alcohol exposure may aid in developing more targeted and effective pharmacological interventions for AUD. Results also highlight the importance in including sex as a biological variable in AUD research, particularly when examining immune function.<\/jats:p>","DOI":"10.1101\/2025.05.21.655347","type":"posted-content","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T05:30:13Z","timestamp":1748323813000},"source":"Crossref","is-referenced-by-count":1,"title":["Peripheral blood cell-type and sex-specific signatures of alcohol misuse revealed by single-cell transcriptomics"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8790-7649","authenticated-orcid":false,"given":"Amol C.","family":"Shetty","sequence":"first","affiliation":[{"name":"Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Verma","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Sivinski","sequence":"additional","affiliation":[{"name":"Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn","family":"Doty","sequence":"additional","affiliation":[{"name":"Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke","family":"Hollander","sequence":"additional","affiliation":[{"name":"Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Roche","sequence":"additional","affiliation":[{"name":"Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chamindi","family":"Seneviratne","sequence":"additional","affiliation":[{"name":"Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD"},{"name":"Division of Treatment ant Recovery, National Institutes of Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041123364518000_2025.05.21.655347v1.1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1360-0443.2012.04054.x"},{"key":"2026041123364518000_2025.05.21.655347v1.2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0087366"},{"key":"2026041123364518000_2025.05.21.655347v1.3","unstructured":"NIAAA. 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