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

doi:10.1038/ng.3417

Comparative Study

. 2015 Dec;47(12):1443-8.

doi: 10.1038/ng.3417. Epub 2015 Oct 19.

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

Stephan Buch¹, Felix Stickel², Eric Trépo^{3

4}, Michael Way^{5

6}, Alexander Herrmann¹, Hans Dieter Nischalke⁷, Mario Brosch¹, Jonas Rosendahl⁸, Thomas Berg⁸, Monika Ridinger^{9

10}, Marcella Rietschel¹¹, Andrew McQuillin⁶, Josef Frank¹¹, Falk Kiefer¹¹, Stefan Schreiber¹², Wolfgang Lieb¹³, Michael Soyka¹⁴, Nasser Semmo¹⁵, Elmar Aigner¹⁶, Christian Datz¹⁶, Renate Schmelz¹, Stefan Brückner¹, Sebastian Zeissig¹, Anna-Magdalena Stephan¹, Norbert Wodarz⁹, Jacques Devière^{3

4}, Nicolas Clumeck¹⁷, Christoph Sarrazin¹⁸, Frank Lammert¹⁹, Thierry Gustot^{3

4}, Pierre Deltenre^{3

20

21}, Henry Völzke²², Markus M Lerch²³, Julia Mayerle²³, Florian Eyer²⁴, Clemens Schafmayer²⁵, Sven Cichon²⁶, Markus M Nöthen^{27

28}, Michael Nothnagel²⁹, David Ellinghaus³⁰, Klaus Huse³¹, Andre Franke³⁰, Steffen Zopf³², Claus Hellerbrand³³, Christophe Moreno^{3

4}, Denis Franchimont^{3

4}, Marsha Y Morgan⁵, Jochen Hampe¹

Affiliations

¹ Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
² Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.
³ Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles (CUB) Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
⁴ Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
⁵ UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK.
⁶ Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
⁷ Department of Internal Medicine I, University of Bonn, Bonn, Germany.
⁸ Section of Hepatology, University Hospital Leipzig, Leipzig, Germany.
⁹ Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.
¹⁰ Psychiatric Health Care Aargau, Psychiatrische Dienste Aargau, Windisch, Switzerland.
¹¹ Central Institute of Mental Health, University of Heidelberg, Faculty of Medicine Mannheim, Mannheim, Germany.
¹² Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
¹³ Institute of Epidemiology and Biobank PopGen, Christian Albrechts University Kiel, Kiel, Germany.
¹⁴ Psychiatric Hospital, Ludwig Maximilians University, Munich, Germany.
¹⁵ Department of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland.
¹⁶ Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Salzburg, Austria.
¹⁷ Centre Hospitalier Le Domaine, Université Libre de Bruxelles, Braine-l'Alleud, Belgium.
¹⁸ Department of Gastroenterology, University Hospital Frankfurt, Frankfurt, Germany.
¹⁹ Department of Medicine II, Saarland University Hospital, Homburg, Germany.
²⁰ Service d'Hépato-Gastroentérologie, Hôpital de Jolimont, Haine-Saint-Paul, Belgium.
²¹ Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
²² Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
²³ Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany.
²⁴ Department of Clinical Toxicology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
²⁵ Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
²⁶ Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
²⁷ Institute of Human Genetics, University of Bonn, Bonn, Germany.
²⁸ Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
²⁹ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
³⁰ Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
³¹ Fritz Lipmann Institute of Age Research (FLI), Jena, Germany.
³² Department of Internal Medicine 1, University Hospital Erlangen, Erlangen, Germany.
³³ Department of Internal Medicine 1, University Hospital Regensburg, Regensburg, Germany.

PMID: 26482880
DOI: 10.1038/ng.3417

Free article

Comparative Study

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

Stephan Buch et al. Nat Genet. 2015 Dec.

Free article

. 2015 Dec;47(12):1443-8.

doi: 10.1038/ng.3417. Epub 2015 Oct 19.

Authors

Affiliations

¹ Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
² Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.
³ Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles (CUB) Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
⁴ Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
⁵ UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK.
⁶ Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
⁷ Department of Internal Medicine I, University of Bonn, Bonn, Germany.
⁸ Section of Hepatology, University Hospital Leipzig, Leipzig, Germany.
⁹ Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.
¹⁰ Psychiatric Health Care Aargau, Psychiatrische Dienste Aargau, Windisch, Switzerland.
¹¹ Central Institute of Mental Health, University of Heidelberg, Faculty of Medicine Mannheim, Mannheim, Germany.
¹² Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
¹³ Institute of Epidemiology and Biobank PopGen, Christian Albrechts University Kiel, Kiel, Germany.
¹⁴ Psychiatric Hospital, Ludwig Maximilians University, Munich, Germany.
¹⁵ Department of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland.
¹⁶ Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Salzburg, Austria.
¹⁷ Centre Hospitalier Le Domaine, Université Libre de Bruxelles, Braine-l'Alleud, Belgium.
¹⁸ Department of Gastroenterology, University Hospital Frankfurt, Frankfurt, Germany.
¹⁹ Department of Medicine II, Saarland University Hospital, Homburg, Germany.
²⁰ Service d'Hépato-Gastroentérologie, Hôpital de Jolimont, Haine-Saint-Paul, Belgium.
²¹ Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
²² Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
²³ Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany.
²⁴ Department of Clinical Toxicology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
²⁵ Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
²⁶ Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
²⁷ Institute of Human Genetics, University of Bonn, Bonn, Germany.
²⁸ Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
²⁹ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
³⁰ Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
³¹ Fritz Lipmann Institute of Age Research (FLI), Jena, Germany.
³² Department of Internal Medicine 1, University Hospital Erlangen, Erlangen, Germany.
³³ Department of Internal Medicine 1, University Hospital Regensburg, Regensburg, Germany.

PMID: 26482880
DOI: 10.1038/ng.3417

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.

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Comment in

Liver: New genetic insights into the development of alcohol-related cirrhosis.
Weber C. Weber C. Nat Rev Gastroenterol Hepatol. 2015 Dec;12(12):672. doi: 10.1038/nrgastro.2015.190. Epub 2015 Nov 3. Nat Rev Gastroenterol Hepatol. 2015. PMID: 26526123 No abstract available.

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References

1. Nat Genet. 2011 Jan;43(1):17-9 - PubMed
1. Nat Genet. 2006 Aug;38(8):904-9 - PubMed
1. Diabetes. 2012 Feb;61(2):281-91 - PubMed
1. Stat Med. 2002 Jun 15;21(11):1539-58 - PubMed
1. Hepatology. 2015 Jan;61(1):108-18 - PubMed

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[1] Nat Genet. 2011 Jan;43(1):17-9 - PubMed

[2] Nat Genet. 2011 Jan;43(1):17-9 - PubMed

[3] Nat Genet. 2006 Aug;38(8):904-9 - PubMed

[4] Nat Genet. 2006 Aug;38(8):904-9 - PubMed

[5] Diabetes. 2012 Feb;61(2):281-91 - PubMed

[6] Diabetes. 2012 Feb;61(2):281-91 - PubMed

[7] Stat Med. 2002 Jun 15;21(11):1539-58 - PubMed

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[9] Hepatology. 2015 Jan;61(1):108-18 - PubMed

[10] Hepatology. 2015 Jan;61(1):108-18 - PubMed

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

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

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