A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis

• Published in: Nature genetics Vol. 47; no. 12; pp. 1443 - 1448
• Main Authors: 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, Brückner, Stefan, Zeissig, Sebastian, Stephan, Anna-Magdalena, Wodarz, Norbert, Devière, Jacques, Clumeck, Nicolas, Sarrazin, Christoph, 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, Franke, Andre, Zopf, Steffen, Hellerbrand, Claus, Moreno, Christophe, Franchimont, Denis, Morgan, Marsha Y, Hampe, Jochen
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2015; Nature Publishing Group
• Subjects: 45; 45/43; 692/699/1503; 692/699/1503/1607/1608; Acyltransferases - genetics; Adult; Aged; Agriculture; Alcohol; Alcohols; Animal Genetics and Genomics; Bioinformatics; Biomedicine; Body mass index; Cancer Research; Case-Control Studies; Confidence intervals; Diabetes; Disease susceptibility; Female; Gene Function; Genetic aspects; Genetic Predisposition to Disease; Genetic variation; Genome-Wide Association Study; Genomes; Health aspects; Human Genetics; Humans; Identification and classification; letter; Lipase - genetics; Lipid metabolism; Liver cirrhosis; Liver Cirrhosis, Alcoholic - genetics; Liver diseases; Liver transplantation; Male; Membrane Proteins - genetics; Meta-analysis; Middle Aged; Polymorphism, Single Nucleotide - genetics; Population; Risk Factors; United Kingdom > UK
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3417

Felix Stickel and colleagues report the results of a genome-wide association study of alcohol-related cirrhosis. They confirm PNPLA3 as a susceptibility locus and identify new association signals in MBOAT7 and TM6SF2 . Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world 1 , 2 , 3 . 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.