Hamish Innes1, Stephan Buch2, Sharon Hutchinson3, Indra Neil Guha4, Joanne R Morling5, Eleanor Barnes6, Will Irving4, Ewan Forrest7, Vincent Pedergnana8, David Goldberg3, Esther Aspinall3, Stephan Barclay7, Peter C Hayes9, John Dillon10, Hans Dieter Nischalke11, Philipp Lutz11, Ulrich Spengler11, Janett Fischer12, Thomas Berg12, Mario Brosch2, Florian Eyer13, Christian Datz14, Sebastian Mueller15, Teresa Peccerella15, Pierre Deltenre16, Astrid Marot16, Michael Soyka17, Andrew McQuillin18, Marsha Y Morgan19, Jochen Hampe2, Felix Stickel20. 1. School of Health and Life Sciences, Glasgow Caledonian University, Glasgow United Kingdom; Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom; Health Protection Scotland, Glasgow, United Kingdom. Electronic address: Hamish.Innes@gcu.ac.uk. 2. Medical Department 1, University Hospital Dresden, Technische Universität Dresden, Germany. 3. School of Health and Life Sciences, Glasgow Caledonian University, Glasgow United Kingdom; Health Protection Scotland, Glasgow, United Kingdom. 4. National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom. 5. Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom; National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom. 6. Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, and the Oxford National Institute for Health Research Biomedical Research Centre, Oxford University, United Kingdom. 7. Glasgow Royal Infirmary, Glasgow, United Kingdom. 8. Laboratoire Maladies Infectieuses et Vecteurs Écologie, Génétique, Évolution et Contrôl (UMR CNRS 5290, UR IRD 224, UM), Montpellier, France. 9. Royal Infirmary Edinburgh, Edinburgh, United Kingdom. 10. School of Medicine, University of Dundee, Dundee, United Kingdom. 11. Department of Internal Medicine I, University of Bonn, Bonn, Germany. 12. Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany. 13. Department of Clinical Toxicology, Klinikum Rechts der Isar, Technical University of Munich, Germany. 14. Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private Medical University of Salzburg, Oberndorf, Austria. 15. Department of Internal Medicine and Center for Alcohol Research, Salem Medical Center University Hospital Heidelberg, Heidelberg, Germany. 16. Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland. 17. Psychiatric hospital, University of Munich, Munich, Germany, and Department of Psychiatry, Meiringen Hospital, Meiringen, Switzerland. 18. Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, United Kingdom. 19. Division of Medicine, University College London Institute for Liver & Digestive Health, Royal Free Campus, University College London, London, United Kingdom. 20. Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.
Abstract
BACKGROUND AND AIMS: Little is known about genetic factors that affect development of alcohol-related cirrhosis. We performed a genome-wide association study (GWAS) of samples from the United Kingdom Biobank (UKB) to identify polymorphisms associated with risk of alcohol-related liver disease. METHODS: We performed a GWAS of 35,839 participants in the UKB with high intake of alcohol against markers of hepatic fibrosis (FIB-4, APRI, and Forns index scores) and hepatocellular injury (levels of aminotransferases). Loci identified in the discovery analysis were tested for their association with alcohol-related cirrhosis in 3 separate European cohorts (phase 1 validation cohort; n=2545). Variants associated with alcohol-related cirrhosis in the validation at a false discovery rate of less than 20% were then directly genotyped in 2 additional European validation cohorts (phase 2 validation, n=2068). RESULTS: In the GWAS of the discovery cohort, we identified 50 independent risk loci with genome-wide significance (P < 5 × 10-8). Nine of these loci were significantly associated with alcohol-related cirrhosis in the phase 1 validation cohort; 6 of these 9 loci were significantly associated with alcohol-related cirrhosis in phase 2 validation cohort, at a false discovery rate below 5%. The loci included variants in the mitochondrial amidoxime reducing component 1 gene (MARC1) and the heterogeneous nuclear ribonucleoprotein U like 1 gene (HNRNPUL1). After we adjusted for age, sex, body mass index, and type-2 diabetes in the phase 2 validation cohort, the minor A allele of MARC1:rs2642438 was associated with reduced risk of alcohol-related cirrhosis (adjusted odds ratio, 0.76; P=.0027); conversely, the minor C allele of HNRNPUL1:rs15052 was associated with an increased risk of alcohol-related cirrhosis (adjusted odds ratio, 1.30; P=.020). CONCLUSIONS: In a GWAS of samples from the UKB, we identified and validated (in 5 European cohorts) single-nucleotide polymorphisms that affect risk of alcohol-related cirrhosis in opposite directions: the minor A allele in MARC1:rs2642438 decreases risk, whereas the minor C allele in HNRNPUL1:rs15052 increases risk.
BACKGROUND AND AIMS: Little is known about genetic factors that affect development of alcohol-related cirrhosis. We performed a genome-wide association study (GWAS) of samples from the United Kingdom Biobank (UKB) to identify polymorphisms associated with risk of alcohol-related liver disease. METHODS: We performed a GWAS of 35,839 participants in the UKB with high intake of alcohol against markers of hepatic fibrosis (FIB-4, APRI, and Forns index scores) and hepatocellular injury (levels of aminotransferases). Loci identified in the discovery analysis were tested for their association with alcohol-related cirrhosis in 3 separate European cohorts (phase 1 validation cohort; n=2545). Variants associated with alcohol-related cirrhosis in the validation at a false discovery rate of less than 20% were then directly genotyped in 2 additional European validation cohorts (phase 2 validation, n=2068). RESULTS: In the GWAS of the discovery cohort, we identified 50 independent risk loci with genome-wide significance (P < 5 × 10-8). Nine of these loci were significantly associated with alcohol-related cirrhosis in the phase 1 validation cohort; 6 of these 9 loci were significantly associated with alcohol-related cirrhosis in phase 2 validation cohort, at a false discovery rate below 5%. The loci included variants in the mitochondrial amidoxime reducing component 1 gene (MARC1) and the heterogeneous nuclear ribonucleoprotein U like 1 gene (HNRNPUL1). After we adjusted for age, sex, body mass index, and type-2 diabetes in the phase 2 validation cohort, the minor A allele of MARC1:rs2642438 was associated with reduced risk of alcohol-related cirrhosis (adjusted odds ratio, 0.76; P=.0027); conversely, the minor C allele of HNRNPUL1:rs15052 was associated with an increased risk of alcohol-related cirrhosis (adjusted odds ratio, 1.30; P=.020). CONCLUSIONS: In a GWAS of samples from the UKB, we identified and validated (in 5 European cohorts) single-nucleotide polymorphisms that affect risk of alcohol-related cirrhosis in opposite directions: the minor A allele in MARC1:rs2642438 decreases risk, whereas the minor C allele in HNRNPUL1:rs15052 increases risk.
Authors: Alexis C Edwards; Kristina Sundquist; Jan Sundquist; Kenneth S Kendler; Sara Larsson Lönn Journal: Alcohol Clin Exp Res Date: 2021-12-19 Impact factor: 3.455
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Authors: Mary E Haas; James P Pirruccello; Samuel N Friedman; Minxian Wang; Connor A Emdin; Veeral H Ajmera; Tracey G Simon; Julian R Homburger; Xiuqing Guo; Matthew Budoff; Kathleen E Corey; Alicia Y Zhou; Anthony Philippakis; Patrick T Ellinor; Rohit Loomba; Puneet Batra; Amit V Khera Journal: Cell Genom Date: 2021-12-08
Authors: Bernd Schnabl; Gavin E Arteel; Felix Stickel; Jan Hengstler; Nachiket Vartak; Ahmed Ghallab; Steven Dooley; Yujia Li; Robert F Schwabe Journal: Z Gastroenterol Date: 2022-01-18 Impact factor: 1.769
Authors: Carolin V Schneider; Kai Markus Schneider; Donna M Conlon; Joseph Park; Marijana Vujkovic; Inuk Zandvakili; Yi-An Ko; Christian Trautwein; Regerneron Center; Rotonya M Carr; Pavel Strnad; Christoph A Thaiss; Daniel J Rader Journal: Med (N Y) Date: 2021-07-09
Authors: Pierre Deltenre; Jochen Hampe; Felix Stickel; Stephan Buch; Hamish Innes; Hans Dieter Nischalke; Indra Neil Guha; Karl Heinz Weiss; Will Irving; Daniel Gotthardt; Eleanor Barnes; Janett Fischer; M Azim Ansari; Jonas Rosendahl; Shang-Kuan Lin; Astrid Marot; Vincent Pedergnana; Markus Casper; Jennifer Benselin; Frank Lammert; John McLauchlan; Philip L Lutz; Victoria Hamill; Sebastian Mueller; Joanne R Morling; Georg Semmler; Florian Eyer; Johann von Felden; Alexander Link; Arndt Vogel; Jens U Marquardt; Stefan Sulk; Jonel Trebicka; Luca Valenti; Christian Datz; Thomas Reiberger; Clemens Schafmayer; Thomas Berg Journal: Hepatol Commun Date: 2021-12-27
Authors: Kevin Teo; Kushala W M Abeysekera; Leon Adams; Elmar Aigner; Quentin M Anstee; Jesus M Banales; Rajarshi Banerjee; Priyadarshi Basu; Thomas Berg; Pallav Bhatnagar; Stephan Buch; Ali Canbay; Sonia Caprio; Ankita Chatterjee; Yii-Der Ida Chen; Abhijit Chowdhury; Ann K Daly; Christian Datz; Dana de Gracia Hahn; Johanna K DiStefano; Jiawen Dong; Amedine Duret; Connor Emdin; Madison Fairey; Glenn S Gerhard; Xiuqing Guo; Jochen Hampe; Matthew Hickman; Lena Heintz; Christian Hudert; Harriet Hunter; Matt Kelly; Julia Kozlitina; Marcin Krawczyk; Frank Lammert; Claudia Langenberg; Joel Lavine; Lin Li; Hong Kai Lim; Rohit Loomba; Panu K Luukkonen; Phillip E Melton; Trevor A Mori; Nicholette D Palmer; Constantinos A Parisinos; Sreekumar G Pillai; Faiza Qayyum; Matthias C Reichert; Stefano Romeo; Jerome I Rotter; Yu Ri Im; Nicola Santoro; Clemens Schafmayer; Elizabeth K Speliotes; Stefan Stender; Felix Stickel; Christopher D Still; Pavel Strnad; Kent D Taylor; Anne Tybjærg-Hansen; Giuseppina Rosaria Umano; Mrudula Utukuri; Luca Valenti; Lynne E Wagenknecht; Nicholas J Wareham; Richard M Watanabe; Julia Wattacheril; Hanieh Yaghootkar; Hannele Yki-Järvinen; Kendra A Young; Jake P Mann Journal: J Hepatol Date: 2020-08-31 Impact factor: 25.083