Genome‐wide significant association between alcohol dependence and a variant in the ADH gene cluster
Open accessAbstract
Alcohol dependence (AD) is an important contributory factor to the global burden of disease. The etiology of AD involves both environmental and genetic factors, and the disorder has a heritability of around 50%. The aim of the present study was to identify susceptibility genes for AD by performing a genome‐wide association study (GWAS). The sample comprised 1333 male in‐patients with severe AD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and 2168 controls. These included 487 patients and 1358 controls from a previous GWAS study by our group. All individuals were of German descent. Single‐marker tests and a polygenic score‐based analysis to assess the combined contribution of multiple markers with small effects were performed. The single nucleotide polymorphism (SNP) rs1789891, which is located between the ADH1B and ADH1C genes, achieved genome‐wide significance [P = 1.27E–8, odds ratio (OR) = 1.46]. Other markers from this region were also associated with AD, and conditional analyses indicated that these made a partially independent contribution. The SNP rs1789891 is in complete linkage disequilibrium with the functional Arg272Gln variant (P = 1.24E–7, OR = 1.31) of the ADH1C gene, which has been reported to modify the rate of ethanol oxidation to acetaldehyde in vitro. A polygenic score‐based approach produced a significant result (P = 9.66E–9). This is the first GWAS of AD to provide genome‐wide significant support for the role of the ADH gene cluster and to suggest a polygenic component to the etiology of AD. The latter result may indicate that many more AD susceptibility genes still await identification.
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Several additional variants prioritized in conditional analysis were in moderate to strong LD with rs698, a functional ADH1C variant with a role in AD.
“Several additional variants that were prioritized in the conditional analysis, while not significant, were in moderate to strong LD with rs698 (marginal odds ratio = 1.115, SE = .021, z = 5.19, p = 2.1E-7; conditional odds ratio = 1.084, SE = .021, z = 3.78, p = 1.6E-4), a functional ADH1C variant with a role in AD8,11.”
From Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders (2018) · cites this paper as [11]
Variants in the genes responsible for alcohol metabolism, especially ADH1B and ALDH2, have been strongly implicated in alcohol dependence.
“Variants in the genes responsible for alcohol metabolism, especially ADH1B and ALDH2, have been strongly implicated8–13.”
From Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders (2018) · cites this paper as [11]
GWAS in East Asian samples confirmed the role of ALDH2 in alcohol consumption.
“For alcohol consumption, GWAS in East Asian samples confirmed the role of ALDH2, 98,99”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [98]
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- Authors
- Frank, J., Cichon, S., Treutlein, J., Ridinger, M., Mattheisen, M., Hoffmann, P., Herms, S., Wodarz, N., Soyka, M., Zill, P., Maier, W., Mössner, R., Gaebel, W., Dahmen, N., Scherbaum, N., Schmäl, C., Steffens, M., Lucae, S., Ising, M., Müller‐Myhsok, B., Nöthen, M. M., Mann, K., Kiefer, F., & Rietschel, M.
- Affiliations
- Heidelberg University (DE)
- University of Bonn (DE)
- University Hospital Regensburg (DE)
- Privatklinik Meiringen (CH)
- Ludwig-Maximilians-Universität München (DE)
- Johannes Gutenberg University Mainz (DE)
- University of Duisburg-Essen (DE)
- Max Planck Institute of Psychiatry (DE)
- Corresponding author
- Rietschel, Marcella
- ORCID
- Venue
- Addiction Biology
- Publisher
- Wiley
- Published
- 2011-10-18
- Volume
- 17
- Issue
- 1
- Pages
- 171-180
- ISSN
- 1355-6215 (ISSN-L)
- 1369-1600
- PMC
- PMC3245349
- OpenAlex
- W1585065066
- Cited by
- 176
- References
- 29
- Citations by year
- 2025: 7 · 2024: 9 · 2023: 8 · 2022: 7 · 2021: 5 · 2020: 4 · 2019: 10 · 2018: 16 · 2017: 18 · 2016: 19 · 2015: 17 · 2014: 24 · 2013: 22 · 2012: 9
- FWCI
- 11.17
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Addiction Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- JuSER (Forschungszentrum Jülich) (submittedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (P50AA011998, P60AA011998, R01AA013320, U10AA008401)
- National Heart, Lung, and Blood Institute (U01HL089856)
- National Institute of Mental Health (R01MH087590, R01MH081862)
- National Institute on Drug Abuse (R01DA013423)
- National Human Genome Research Institute (U01HG004422, U01HG004446, U01HG004438, HHSN268200782096C)
- National Cancer Institute (P01CA089392)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- alcoholism, ADH1B, ADH1C, acetaldehyde oxidation, genetic susceptibility, polygenic risk score, linkage disequilibrium, alcohol use disorder genetics
- MeSH terms
- Adult, Alcohol Dehydrogenase, Alcoholism, Multigene Family, Germany, Humans, Male, Odds Ratio, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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