A two-stage genome-wide association study confirms pnpla 3 and identifies tm 6 sf 2 and mboat 7 as risk loci for alcohol-related cirrhosis

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. DOI: https://doi.org/10.1038/ng.3417 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-119315 Accepted Version Originally published at: 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, AnnaMagdalena; 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 (2015). A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nature Genetics, 47(12):1443-1448. DOI: https://doi.org/10.1038/ng.3417 A TWO-STAGE 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 Medical Department 1, University Hospital Dresden, TU Dresden, Germany Department of Gastroenterology and Hepatology, University Hospital of Zurich, Switzerland Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, UK Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, UK Department of Internal Medicine I, University of Bonn, Germany Department of Gastroenterology, University Hospital Leipzig, Germany Dept. of Psychiatry and Psychotherapy, Univ. Regensburg, Germany Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Germany Institute of Epidemiology and Biobank POPGEN, Christian-Albrechts-University Kiel, Germany Psychiatric Hospital, University of Munich, Germany Department of Visceral Surgery and Medicine, Inselspital Bern, Switzerland Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Austria Centre Hospitalier Le Domaine, Université Libre de Bruxelles, Braine-L’Alleud, Belgium Department of Gastroenterology, University Hospital Frankfurt, Frankfurt/Main, Germany Department of Medicine II, University Hospital Homburg, Homburg/Saar, Germany Service d'Hépato-Gastroentérologie, Hôpital de Jolimont, Haine-Saint-Paul, Belgium Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland Institute for Community Medicine, University Medicine Greifswald, Germany Department of Internal Medicine A, University Medicine Greifswald, Germany Department of Clinical Toxicology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Germany Department of Biomedicine, University Hospital Basel, Switzerland Institute of Human Genetics, University of Bonn, Bonn, Germany Buch et al. GWAS of alcohol-related cirrhosis 2 Department of Genomics, Life and Brain Center, University of Bonn, Germany Cologne Center for Genomics, University of Cologne, Germany Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany Fritz-Lipmann Institute of Age Research (FLI), Jena, Germany Department of Internal Medicine 1, University Hospital Erlangen, Germany Department of Internal Medicine 1, University Hospital Regensburg, Germany Psychiatric Health Care Aargau, PDAG, Switzerland S.B., F.S. and E.T. contributed equally to the study and the manuscript D.F., M.Y,M. and J.H. contributed equally to the study and the manuscript and assume equal responsibility for senior authorship To whom correspondence should be addressed: Felix Stickel, MD Department of Gastroenterology and Hepatology University Hospital of Zurich Rämistrasse 100, CH-8091 Zurich / Switzerland Phone +41-31-335 7816, Fax +41-31-335 3519 Email: Felix.stickel@ikp.unibe.ch or felix.stickel@usz.ch Buch et al. GWAS of alcohol-related cirrhosis