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

Stephan Buch, Felix Stickel, Eric Trépo, Michael Way, Alexander Herrmann, Hans Dieter Nischalke, Mario Brosch, Jonas Rosendahl, Thomas Berg, Monika Ridinger, Marcella Rietschel, Andrew McQuillin, Josef Frank, Falk Kiefer, Stefan Schreiber, Wolfgang Lieb, Michael Soyka, Nasser Semmo, Elmar Aigner, Christian Datz, Renate Schmelz, Stefan Brückner, Sebastian Zeissig, Anna-Magdalena Stephan, Norbert Wodarz, Jacques Devière, Nicolas Clumeck, Christoph Sarrazin, Frank Lammert, Thierry Gustot, Pierre Deltenre, Henry Völzke, Markus M Lerch, Julia Mayerle, Florian Eyer, Clemens Schafmayer, Sven Cichon, Markus M Nöthen, Michael Nothnagel, David Ellinghaus, Klaus Huse, Andre Franke, Steffen Zopf, Claus Hellerbrand, Christophe Moreno, Denis Franchimont, Marsha Y Morgan, Jochen Hampe, Stephan Buch, Felix Stickel, Eric Trépo, Michael Way, Alexander Herrmann, Hans Dieter Nischalke, Mario Brosch, Jonas Rosendahl, Thomas Berg, Monika Ridinger, Marcella Rietschel, Andrew McQuillin, Josef Frank, Falk Kiefer, Stefan Schreiber, Wolfgang Lieb, Michael Soyka, Nasser Semmo, Elmar Aigner, Christian Datz, Renate Schmelz, Stefan Brückner, Sebastian Zeissig, Anna-Magdalena Stephan, Norbert Wodarz, Jacques Devière, Nicolas Clumeck, Christoph Sarrazin, Frank Lammert, Thierry Gustot, Pierre Deltenre, Henry Völzke, Markus M Lerch, Julia Mayerle, Florian Eyer, Clemens Schafmayer, Sven Cichon, Markus M Nöthen, Michael Nothnagel, David Ellinghaus, Klaus Huse, Andre Franke, Steffen Zopf, Claus Hellerbrand, Christophe Moreno, Denis Franchimont, Marsha Y Morgan, Jochen Hampe

Abstract

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.

References

    1. Nat Genet. 2011 Jan;43(1):17-9
    1. Nat Genet. 2006 Aug;38(8):904-9
    1. Diabetes. 2012 Feb;61(2):281-91
    1. Stat Med. 2002 Jun 15;21(11):1539-58
    1. Hepatology. 2015 Jan;61(1):108-18
    1. Am J Hum Genet. 2013 Dec 5;93(6):1027-34
    1. Hepatology. 2011 Jan;53(1):346-55
    1. Aliment Pharmacol Ther. 2008 Nov 15;28(10):1188-98
    1. Gastroenterology. 2012 Nov;143(5):1244-52.e1-12
    1. PLoS One. 2014 Jul 22;9(7):e97589
    1. Hum Genet. 2012 Jan;131(1):111-9
    1. Arch Gen Psychiatry. 2009 Jul;66(7):773-84
    1. Mol Med. 2011;17 (11-12):1285-94
    1. Am J Hum Genet. 2009 Dec;85(6):847-61
    1. Hepatology. 2011 Jan;53(1):86-95
    1. Hepatology. 2002 Jul;36(1):227-42
    1. Alcohol Clin Exp Res. 1991 Feb;15(1):45-66
    1. Am J Transplant. 2010 Jan;10(1):138-48
    1. J Hepatol. 2013 Aug;59(2):344-50
    1. Alcohol Clin Exp Res. 1981 Spring;5(2):207-15
    1. Addict Biol. 2015 May;20(3):594-604
    1. Hepatology. 2006 Feb;43(2):352-61
    1. Nat Genet. 2010 Jan;42(1):21-3
    1. Ann Intern Med. 2009 Feb 3;150(3):153-61
    1. PLoS Genet. 2011 May;7(5):e1002078
    1. Nat Genet. 2009 Jul;41(7):816-9
    1. Aliment Pharmacol Ther. 2014 Sep;40(6):571-81
    1. N Engl J Med. 2012 Feb 2;366(5):478-9; author reply 479
    1. J Biol Chem. 2008 Oct 31;283(44):30235-45
    1. J Hepatol. 2014 Nov;61(5):1073-9
    1. Nat Genet. 2007 Aug;39(8):995-9
    1. J Biol Chem. 2010 Feb 26;285(9):6706-15
    1. Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5082-7
    1. Lancet. 1995 Oct 14;346(8981):987-90
    1. Nat Genet. 2008 Dec;40(12):1461-5
    1. Nature. 2007 Jun 7;447(7145):661-78
    1. Bioinformatics. 2010 Sep 15;26(18):2336-7
    1. Am J Gastroenterol. 2015 Jun;110(6):846-56
    1. J Hepatol. 2013 Jul;59(1):160-8
    1. Hepatology. 2015 Feb;61(2):506-14
    1. Alcohol Clin Exp Res. 1996 Dec;20(9):1528-33
    1. Nat Rev Gastroenterol Hepatol. 2013 Aug;10 (8):487-94
    1. Nat Commun. 2014 Jun 30;5:4309
    1. Hum Mol Genet. 2014 Aug 1;23(15):4077-85
    1. Nat Genet. 2011 Mar 13;43(4):329-32
    1. PLoS Genet. 2009 Jun;5(6):e1000529
    1. PLoS Genet. 2011 Mar;7(3):e1001324
    1. J Biol Chem. 2003 Aug 8;278(32):30382-93
    1. Nat Genet. 2014 Apr;46(4):352-6

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