Identification of risk variants and cross-disorder pleiotropy through multi-ancestry genome-wide analysis of alcohol use disorder

dc.contributor.authorIcick, Romain
dc.contributor.authorShadrin, Alexey
dc.contributor.authorHolen, Børge
dc.contributor.authorKaradag, Naz
dc.contributor.authorParker, Nadine
dc.contributor.authorO'Connell, Kevin S.
dc.contributor.authorFrei, Oleksandr
dc.contributor.authorBahrami, Shahram
dc.contributor.authorCollier Høegh, Margrethe
dc.contributor.authorVik Lagerberg, Trine
dc.contributor.authorCheng, Weiqiu
dc.contributor.authorSeibert, Tyler M.
dc.contributor.authorDjurovic, Srdjan
dc.contributor.authorDale, Anders M.
dc.contributor.authorZhou, Hang
dc.contributor.authorEdenberg, Howard J.
dc.contributor.authorGelernter, Joel
dc.contributor.authorSmeland, Olav B.
dc.contributor.authorHindley, Guy
dc.contributor.authorAndreassen, Ole A.
dc.contributor.departmentBiochemistry and Molecular Biology, School of Medicine
dc.date.accessioned2025-06-17T14:02:00Z
dc.date.available2025-06-17T14:02:00Z
dc.date.issued2025
dc.description.abstractAlcohol use disorder (AUD) is highly heritable and burdensome worldwide. Genome-wide association studies (GWASs) can provide new evidence regarding the aetiology of AUD. We report a multi-ancestry GWAS focusing on a narrow AUD phenotype, using novel statistical tools in a total sample of 1,041,450 individuals [102,079 cases; European, 75,583; African, 20,689 (mostly African-American); Hispanic American, 3,449; East Asian, 2,254; South Asian, 104; descent]. Cross-ancestry functional analyses were performed with European and African samples. Thirty-seven genome-wide significant loci (105 variants) were identified, of which seven were novel for AUD and six for other alcohol phenotypes. Loci were mapped to genes, which show altered expression in brain regions relevant for AUD (striatum, hypothalamus, and prefrontal cortex) and encode potential drug targets (GABAergic, dopaminergic and serotonergic neurons). African-specific analysis yielded a unique pattern of immune-related gene sets. Polygenic overlap and positive genetic correlations showed extensive shared genetic architecture between AUD and both mental and general medical phenotypes, suggesting they are not only complications of alcohol use but also share genetic liability with AUD. Leveraging a cross-ancestry approach allowed identification of novel genetic loci for AUD and underscores the value of multi-ancestry genetic studies. These findings advance our understanding of AUD risk and clinically-relevant comorbidities.
dc.eprint.versionAuthor's manuscript
dc.identifier.citationIcick R, Shadrin A, Holen B, et al. Identification of risk variants and cross-disorder pleiotropy through multi-ancestry genome-wide analysis of alcohol use disorder. Nat Ment Health. 2025;3(2):253-265. doi:10.1038/s44220-024-00353-8
dc.identifier.urihttps://hdl.handle.net/1805/48812
dc.language.isoen_US
dc.publisherSpringer Nature
dc.relation.isversionof10.1038/s44220-024-00353-8
dc.relation.journalNature Mental Health
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectAlcohol use disorder (AUD)
dc.subjectGenome-wide association studies (GWASs)
dc.subjectGenome-wide significant loci
dc.subjectGenetics
dc.titleIdentification of risk variants and cross-disorder pleiotropy through multi-ancestry genome-wide analysis of alcohol use disorder
dc.typeArticle
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