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A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis
Open accessAbstract
Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.
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“Membrane-bound O-acyltransferase 7 (Mboat7) encodes a phospholipid synthetic enzyme identified through GWAS7,8.”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [7]
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“Additionally, after the initial discovery of Membrane Bound O-Acyltransferase Domain Containing 7 (MBOAT7) as a risk gene for alcohol-related cirrhosis, MBOAT7 allele rs641738 was subsequently verified as a risk factor for MASH (137-139).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [137]
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Metadata
- Authors
- Buch, S., Stickel, F., Trépo, E., Way, M., Herrmann, A., Nischalke, H. D., Brosch, M., Rosendahl, J., Berg, T., Ridinger, M., Rietschel, M., McQuillin, A., Frank, J., Kiefer, F., Schreiber, S., Lieb, W., Soyka, M., Semmo, N., Aigner, E., Datz, C., Schmelz, R., Brückner, S., Zeissig, S., Stephan, A.-M., Wodarz, N., Devière, J., Clumeck, N., Sarrazin, C., Lammert, F., Gustot, T., Deltenre, P., Völzke, H., Lerch, M. M., Mayerle, J., Eyer, F., Schafmayer, C., Cichon, S., Nöthen, M. M., Nothnagel, M., Ellinghaus, D., Huse, K., Franke, A., Zopf, S., Hellerbrand, C., Moreno, C., Franchimont, D., Morgan, M. Y., & Hampe, J.
- Affiliations
- University Hospital Carl Gustav Carus (DE)
- University Hospital Zurich (CH)
- Université Libre de Bruxelles (BE)
- The Royal Free Hospital (GB)
- University of Bonn (DE)
- University Hospital Leipzig (DE)
- Kanton Aargau (CH)
- Heidelberg University (DE)
- University College London (GB)
- University Hospital Schleswig-Holstein (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Ludwig-Maximilians-Universität München (DE)
- University Hospital of Bern (CH)
- University of Salzburg (AT)
- University of Regensburg (DE)
- University Hospital Frankfurt (DE)
- Universitätsklinikum des Saarlandes (DE)
- Universitätsmedizin Greifswald (DE)
- TUM Klinikum (DE)
- University Hospital of Basel (CH)
- University of Cologne (DE)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Universitätsklinikum Erlangen (DE)
- University Hospital Regensburg (DE)
- Corresponding author
- Stickel, Felix
- ORCID
- Buch, Stephan
- Stickel, Felix
- Trépo, Eric
- Way, Michael
- Herrmann, Alexander
- Nischalke, Hans Dieter
- Brosch, Mario
- Rosendahl, Jonas
- Berg, Thomas
- Ridinger, Monika
- Rietschel, Marcella
- McQuillin, Andrew
- Frank, Josef
- Kiefer, Falk
- Schreiber, Stefan
- Lieb, Wolfgang
- Soyka, Michael
- Semmo, Nasser
- Aigner, Elmar
- Datz, Christian
- Schmelz, Renate
- Zeissig, Sebastian
- Wodarz, Norbert
- Lammert, Frank
- Gustot, Thierry
- Deltenre, Pierre
- Völzke, Henry
- Lerch, Markus M
- Mayerle, Julia
- Eyer, Florian
- Schafmayer, Clemens
- Cichon, Sven
- Nöthen, Markus M
- Nothnagel, Michael
- Ellinghaus, David
- Huse, Klaus
- Hellerbrand, Claus
- Moreno, Christophe
- Franchimont, Denis
- Morgan, Marsha Y
- Hampe, Jochen
- Venue
- Nature Genetics
- Published
- 2015-10-19
- Volume
- 47
- Issue
- 12
- Pages
- 1443-1448
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1830916533
- Cited by
- 565
- References
- 49
- Citations by year
- 2026: 30 · 2025: 38 · 2024: 51 · 2023: 72 · 2022: 54 · 2021: 69 · 2020: 82 · 2019: 57 · 2018: 44 · 2017: 43 · 2016: 21 · 2015: 2
- FWCI
- 29.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.zora.uzh.ch
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- IRIS (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Eye Institute (01EY1103)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Keywords
- alcoholic cirrhosis, PNPLA3, MBOAT7, TM6SF2, genetic susceptibility loci, rs738409, lipid metabolism, alcohol abuse
- MeSH terms
- Acyltransferases, Adult, Aged, Female, Humans, Lipase, Liver Cirrhosis, Alcoholic, Male, Membrane Proteins, Middle Aged, Risk Factors, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Phospholipases A2, Calcium-Independent, Genome-Wide Association Study
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