Icick Romain, Shadrin Alexey, Holen Børge, Karadag Naz, Parker Nadine, O'Connell Kevin S, Frei Oleksandr, Bahrami Shahram, Høegh Margrethe Collier, Lagerberg Trine Vik, Cheng Weiqiu, Seibert Tyler M, Djurovic Srdjan, Dale Anders M, Zhou Hang, Edenberg Howard J, Gelernter Joel, Smeland Olav B, Hindley Guy, Andreassen Ole A
NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway.
Université Paris Cité, INSERM U1144, F-75006, France.
Nat Ment Health. 2025 Feb;3(2):253-265. doi: 10.1038/s44220-024-00353-8. Epub 2025 Jan 8.
Alcohol 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.
酒精使用障碍（AUD）在全球范围内具有高度遗传性且负担沉重。全基因组关联研究（GWAS）可为AUD的病因提供新证据。我们报告了一项针对狭义AUD表型的多祖先GWAS，在总共1,041,450名个体的样本中使用了新颖的统计工具[102,079例；欧洲人，75,583例；非洲人，20,689例（大多为非裔美国人）；西班牙裔美国人，3,449例；东亚人，2,254例；南亚人，104例；血统]。对欧洲和非洲样本进行了跨祖先功能分析。确定了37个全基因组显著位点（105个变体），其中7个是AUD的新位点，6个是其他酒精表型的新位点。这些位点被定位到基因上，这些基因在与AUD相关的脑区（纹状体、下丘脑和前额叶皮层）中表达发生改变，并编码潜在的药物靶点（GABA能、多巴胺能和血清素能神经元）。非洲特异性分析产生了独特的免疫相关基因集模式。多基因重叠和正向遗传相关性表明AUD与精神和普通医学表型之间存在广泛的共享遗传结构，这表明它们不仅是酒精使用的并发症，而且与AUD共享遗传易感性。利用跨祖先方法能够识别AUD的新遗传位点，并强调了多祖先基因研究的价值。这些发现推进了我们对AUD风险和临床相关合并症的理解。
