A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 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.
Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
Stephan
S
Buch
Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.
Felix
F
Stickel
Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles (CUB) Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.|Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
Eric
http://orcid.org/0000-0003-0475-3934
E
Trépo
UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK.|Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
Michael
M
Way
Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
Alexander
A
Herrmann
Department of Internal Medicine I, University of Bonn, Bonn, Germany.
Hans Dieter
HD
Nischalke
Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
Mario
M
Brosch
Section of Hepatology, University Hospital Leipzig, Leipzig, Germany.
Jonas
J
Rosendahl
Section of Hepatology, University Hospital Leipzig, Leipzig, Germany.
Thomas
T
Berg
Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.|Psychiatric Health Care Aargau, Psychiatrische Dienste Aargau, Windisch, Switzerland.
Monika
M
Ridinger
Central Institute of Mental Health, University of Heidelberg, Faculty of Medicine Mannheim, Mannheim, Germany.
Marcella
M
Rietschel
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
Andrew
A
McQuillin
Central Institute of Mental Health, University of Heidelberg, Faculty of Medicine Mannheim, Mannheim, Germany.
Josef
J
Frank
Central Institute of Mental Health, University of Heidelberg, Faculty of Medicine Mannheim, Mannheim, Germany.
Falk
F
Kiefer
Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Stefan
S
Schreiber
Institute of Epidemiology and Biobank PopGen, Christian Albrechts University Kiel, Kiel, Germany.
Wolfgang
W
Lieb
Psychiatric Hospital, Ludwig Maximilians University, Munich, Germany.
Michael
M
Soyka
Department of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland.
Nasser
N
Semmo
Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Salzburg, Austria.
Elmar
E
Aigner
Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Salzburg, Austria.
Christian
C
Datz
Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
Renate
R
Schmelz
Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
Stefan
S
Brückner
Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
Sebastian
S
Zeissig
Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
Anna-Magdalena
AM
Stephan
Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.
Norbert
N
Wodarz
Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles (CUB) Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.|Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
Jacques
J
Devière
Centre Hospitalier Le Domaine, Université Libre de Bruxelles, Braine-l'Alleud, Belgium.
Nicolas
N
Clumeck
Department of Gastroenterology, University Hospital Frankfurt, Frankfurt, Germany.
Christoph
C
Sarrazin
Department of Medicine II, Saarland University Hospital, Homburg, Germany.
Frank
F
Lammert
Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles (CUB) Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.|Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
Thierry
T
Gustot
Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles (CUB) Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.|Service d'Hépato-Gastroentérologie, Hôpital de Jolimont, Haine-Saint-Paul, Belgium.|Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
Pierre
P
Deltenre
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Henry
H
Völzke
Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany.
Markus M
MM
Lerch
Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany.
Julia
J
Mayerle
Department of Clinical Toxicology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
Florian
F
Eyer
Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Clemens
C
Schafmayer
Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
Sven
S
Cichon
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
Markus M
MM
Nöthen
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Michael
M
Nothnagel
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
David
D
Ellinghaus
Fritz Lipmann Institute of Age Research (FLI), Jena, Germany.
Klaus
K
Huse
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
Andre
A
Franke
Department of Internal Medicine 1, University Hospital Erlangen, Erlangen, Germany.
Steffen
S
Zopf
Department of Internal Medicine 1, University Hospital Regensburg, Regensburg, Germany.
Claus
C
Hellerbrand
Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles (CUB) Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.|Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
Christophe
C
Moreno
Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles (CUB) Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.|Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
Denis
D
Franchimont
UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK.
Marsha Y
MY
Morgan
Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
Jochen
http://orcid.org/0000-0002-2421-6127
J
Hampe
D000217:Acyltransferases / Q000235:genetics*; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D054512:Phospholipases A2, Calcium-Independent
D000217:Acyltransferases; D008049:Lipase; D008565:Membrane Proteins; C419195:TM6SF2 protein, human; C542776:MBOAT4 protein, human; C533682:PNPLA3 protein, human; D054512:Phospholipases A2, Calcium-Independent