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

被引：0

作者：

Icick, Romain ^{[1
,2
,3
]}

Shadrin, Alexey ^{[1
,2
]}

Holen, Borge ^{[1
,2
]}

Karadag, Naz ^{[1
,2
]}

Parker, Nadine ^{[1
,2
]}

O'Connell, Kevin S. ^{[1
,2
]}

Frei, Oleksandr ^{[1
,2
,4
]}

Bahrami, Shahram ^{[1
,2
]}

Hoegh, Margrethe Collier ^{[1
,2
]}

Lagerberg, Trine Vik ^{[1
,2
]}

Cheng, Weiqiu ^{[1
,2
]}

Seibert, Tyler M. ^{[5
,6
,7
]}

Djurovic, Srdjan ^{[1
,2
,8
,9
]}

Dale, Anders M. ^{[1
,2
,10
,11
,12
,13
]}

Zhou, Hang ^{[14
,15
]}

Edenberg, Howard J. ^{[16
]}

Gelernter, Joel ^{[14
,15
]}

Smeland, Olav B. ^{[1
,2
]}

Hindley, Guy ^{[1
,2
]}

Andreassen, Ole A. ^{[1
,2
,11
]}

机构：

[1] Univ Oslo, Inst Clin Med, NORMENT Ctr, Oslo, Norway

[2] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway

[3] Univ Paris Cite, INSERM, Optimisat therapeut neuropsychopharmacol OPTEN, U1144, Paris, France

[4] Univ Oslo, Ctr Bioinformat, Dept Informat, Oslo, Norway

[5] Univ Calif San Diego, Dept Radiat Med & Appl Sci, La Jolla, CA USA

[6] Univ Calif San Diego, Dept Radiol, La Jolla, CA USA

[7] Univ Calif San Diego, Dept Bioengn, La Jolla, CA USA

[8] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway

[9] Univ Bergen, Ctr Diabet Res, Dept Clin Sci, Bergen, Norway

[10] Univ Calif San Diego, Multimodal Imaging Lab, La Jolla, CA 92037 USA

[11] Univ Oslo, KG Jebsen Ctr Neurodev Disorders, v, Norway

[12] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92037 USA

[13] Univ Calif San Diego, Dept Neurosci, La Jolla, CA USA

[14] Yale Univ, Dept Psychiat, New Haven, CT USA

[15] Vet Affairs Connecticut Healthcare Syst, West Haven, CT USA

[16] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN USA

来源：

NATURE MENTAL HEALTH | 2025年 / 3卷 / 02期

基金：

英国惠康基金;

关键词：

NATIONAL EPIDEMIOLOGIC SURVEY; METAANALYSIS; DISEASES;

D O I：

10.1038/s44220-024-00353-8

中图分类号：

R749 [精神病学];

学科分类号：

100205 ;

摘要：

Alcohol use disorder (AUD) is highly heritable and burdensome worldwide. Genome-wide association studies can provide new evidence regarding the etiology of AUD. We report a multi-ancestry genome-wide association study 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 that 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.

引用

页码：253 / 265

页数：16

共 54 条

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