A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry

Tae-Hwi Schwantes-An¹, John B Whitfield², Guruprasad P Aithal³, Stephen R Atkinson⁴, Ramon Bataller⁵, Greg Botwin^{6

7}, Naga P Chalasani⁸, Heather J Cordell⁹, Ann K Daly¹⁰, Rebecca Darlay⁹, Christopher P Day¹¹, Florian Eyer¹², Tatiana Foroud¹, Samer Gawrieh⁸, Dermot Gleeson¹³, David Goldman¹⁴, Paul S Haber^{15

16}, Jean-Marc Jacquet¹⁷, Craig S Lammert⁸, Tiebing Liang⁸, Suthat Liangpunsakul¹⁸, Steven Masson¹⁰, Philippe Mathurin¹⁹, Romain Moirand²⁰, Andrew McQuillin²¹, Christophe Moreno²², Marsha Y Morgan²³, Sebastian Mueller²⁴, Beat Müllhaupt²⁵, Laura E Nagy²⁶, Pierre Nahon^{27

28

29}, Bertrand Nalpas^{17

30}, Sylvie Naveau³¹, Pascal Perney³², Munir Pirmohamed³³, Helmut K Seitz²⁴, Michael Soyka³⁴, Felix Stickel²⁵, Andrew Thompson^{33

35}, Mark R Thursz⁴, Eric Trépo²², Timothy R Morgan^{36

6}, Devanshi Seth^{15

16

37}; GenomALC Consortium

Affiliations

¹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis IN, USA.
² Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Queensland 4029, Australia.
³ NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals and the University of Nottingham, Nottingham NG7 2UH, UK.
⁴ Department of Metabolism, Digestion & Reproduction, Imperial College London, UK.
⁵ Center for Liver Diseases, University of Pittsburgh Medical Center, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA.
⁶ Department of Veterans Affairs, VA Long Beach Healthcare System, 5901 East Seventh Street, Long Beach, CA 90822, USA.
⁷ F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California CA 90048, USA.
⁸ Department of Medicine, Indiana University, Indianapolis, IN 46202-5175, USA.
⁹ Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
¹⁰ Faculty of Medical Sciences, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
¹¹ Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
¹² Division of Clinical Toxicology, Department of Internal Medicine 2, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany.
¹³ Liver Unit, Sheffield Teaching Hospitals, AO Floor Robert Hadfield Building, Northern General Hospital, Sheffield S5 7AU, UK.
¹⁴ Office of the Clinical Director and Laboratory of Neurogenetics, NIAAA, Bethesda, MD 20952, USA.
¹⁵ Edith Collins Centre (Translational Research in Alcohol Drugs and Toxicology), Sydney Local Health District, Missenden Road, Camperdown, NSW 2050, Australia.
¹⁶ Faculty of Medicine and Health, the University of Sydney, Sydney, NSW 2006, Australia.
¹⁷ Service Addictologie, CHRU Caremeau, 30029 Nîmes, France.
¹⁸ Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University and Roudebush Veterans Administration Medical Center, Indianapolis, USA.
¹⁹ CHRU de Lille, Hôpital Claude Huriez, Rue M. Polonovski CS 70001, 59 037 Lille Cedex, France.
²⁰ Univ Rennes, INRA, INSERM, CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35000 Rennes, France.
²¹ Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London WC1E 6DE, UK.
²² CUB Hôpital Erasme, Université Libre de Bruxelles, clinique d'Hépatologie, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
²³ UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, UK.
²⁴ Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Zeppelinstraße 11-33, 69121 Heidelberg, Germany.
²⁵ Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, CH-8901 Zurich, Switzerland.
²⁶ Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio, OH 44195, USA.
²⁷ Service d'Hépatologie, APHP Hôpital Avicenne et Université Paris 13, Bobigny, France.
²⁸ University Paris 13, Bobigny, France.
²⁹ Inserm U1162 Génomique fonctionnelle des tumeurs solides, Paris, France.
³⁰ DISC, Inserm, 75013 Paris, France.
³¹ Hôpital Antoine-Béclère, 157 Rue de la Porte de Trivaux, 92140 Clamart, France.
³² Hôpital Universitaire Caremeau, Place du Pr. Robert Debre, 30029 Nîmes, France.
³³ MRC Centre for Drug Safety Science, Liverpool Centre for Alcohol Research, University of Liverpool, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, and Liverpool Health Partners, Liverpool, L69 3GL, UK.
³⁴ Psychiatric Hospital University of Munich, Nussbaumsstr.7, 80336 Munich, Germany.
³⁵ Health Analytics, Lane Clark & Peacock LLP, London, UK.
³⁶ Department of Medicine, University of California, Irvine, USA.
³⁷ Centenary Institute of Cancer Medicine and Cell Biology, the University of Sydney, Sydney, NSW 2006, Australia.

PMID: 38727677
PMCID: PMC11093576
DOI: 10.1097/HC9.0000000000000431

A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry

Tae-Hwi Schwantes-An et al. Hepatol Commun. 2024.

. 2024 May 10;8(6):e0431.

doi: 10.1097/HC9.0000000000000431. eCollection 2024 Jun 1.

Authors

Affiliations

¹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis IN, USA.
² Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Queensland 4029, Australia.
³ NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals and the University of Nottingham, Nottingham NG7 2UH, UK.
⁴ Department of Metabolism, Digestion & Reproduction, Imperial College London, UK.
⁵ Center for Liver Diseases, University of Pittsburgh Medical Center, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA.
⁶ Department of Veterans Affairs, VA Long Beach Healthcare System, 5901 East Seventh Street, Long Beach, CA 90822, USA.
⁷ F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California CA 90048, USA.
⁸ Department of Medicine, Indiana University, Indianapolis, IN 46202-5175, USA.
⁹ Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
¹⁰ Faculty of Medical Sciences, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
¹¹ Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
¹² Division of Clinical Toxicology, Department of Internal Medicine 2, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany.
¹³ Liver Unit, Sheffield Teaching Hospitals, AO Floor Robert Hadfield Building, Northern General Hospital, Sheffield S5 7AU, UK.
¹⁴ Office of the Clinical Director and Laboratory of Neurogenetics, NIAAA, Bethesda, MD 20952, USA.
¹⁵ Edith Collins Centre (Translational Research in Alcohol Drugs and Toxicology), Sydney Local Health District, Missenden Road, Camperdown, NSW 2050, Australia.
¹⁶ Faculty of Medicine and Health, the University of Sydney, Sydney, NSW 2006, Australia.
¹⁷ Service Addictologie, CHRU Caremeau, 30029 Nîmes, France.
¹⁸ Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University and Roudebush Veterans Administration Medical Center, Indianapolis, USA.
¹⁹ CHRU de Lille, Hôpital Claude Huriez, Rue M. Polonovski CS 70001, 59 037 Lille Cedex, France.
²⁰ Univ Rennes, INRA, INSERM, CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35000 Rennes, France.
²¹ Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London WC1E 6DE, UK.
²² CUB Hôpital Erasme, Université Libre de Bruxelles, clinique d'Hépatologie, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
²³ UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London NW3 2PF, UK.
²⁴ Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Zeppelinstraße 11-33, 69121 Heidelberg, Germany.
²⁵ Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, CH-8901 Zurich, Switzerland.
²⁶ Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio, OH 44195, USA.
²⁷ Service d'Hépatologie, APHP Hôpital Avicenne et Université Paris 13, Bobigny, France.
²⁸ University Paris 13, Bobigny, France.
²⁹ Inserm U1162 Génomique fonctionnelle des tumeurs solides, Paris, France.
³⁰ DISC, Inserm, 75013 Paris, France.
³¹ Hôpital Antoine-Béclère, 157 Rue de la Porte de Trivaux, 92140 Clamart, France.
³² Hôpital Universitaire Caremeau, Place du Pr. Robert Debre, 30029 Nîmes, France.
³³ MRC Centre for Drug Safety Science, Liverpool Centre for Alcohol Research, University of Liverpool, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, and Liverpool Health Partners, Liverpool, L69 3GL, UK.
³⁴ Psychiatric Hospital University of Munich, Nussbaumsstr.7, 80336 Munich, Germany.
³⁵ Health Analytics, Lane Clark & Peacock LLP, London, UK.
³⁶ Department of Medicine, University of California, Irvine, USA.
³⁷ Centenary Institute of Cancer Medicine and Cell Biology, the University of Sydney, Sydney, NSW 2006, Australia.

PMID: 38727677
PMCID: PMC11093576
DOI: 10.1097/HC9.0000000000000431

Abstract

Background: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis.

Methods: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239).

Results: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis.

Conclusions: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC.

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Conflict of interest statement

Naga P. Chalasani has a number of consulting agreements with and research grants from the pharmaceutical industry, but they are not significantly or directly related to this paper. Munir Pirmohamed receives research funding from various organizations, including the MRC and NIHR. He has also received partnership funding for the following: MRC Clinical Pharmacology Training Scheme (co-funded by MRC and Roche, UCB, Eli Lilly and Novartis); a PhD studentship jointly funded by EPSRC and Astra Zeneca; and grant funding from Vistagen Therapeutics. He has also unrestricted educational grant support for the UK Pharmacogenetics and Stratified Medicine Network from Bristol-Myers Squibb and UCB. He has developed an HLA genotyping panel with MC Diagnostics but does not benefit financially from this. He is part of the IMI Consortium ARDAT (www.ardat.org). None of these funding sources were deployed in the undertaking of this study. Timothy R. Morgan has conducted clinical research with AbbVie, Genfit, Gilead, and Merck but none of these are related to this manuscript. Tae-Hwi Schwantes-An is a paid consultant for Target RWE. Guruprasad P. Aithal consults and advises Clinipace, Servier, Pfizer, GSK, AstraZeneca, DNDi, BenevolentAI, Abbott Product Operations AG, Albireo, PureTech and Merck. RB is on the speakers’ bureau for AbbVie. Samer Gawrieh consults for TransMedics and Pfizer and received grants from Zydus, Viking, and SonicIncytes. Paul S. Haber received grants from Woke Pharmaceuticals. S Masson consults and is on the speakers’ bureau for Norgine and is on the speakers’ bureau for Dr. Falk and Sandoz. Christophe Moreno consults and received grants from AbbVie and Gilead. He consults for Surrozen, Intercept, Echosens, Novartis, Bayer, and Astellas. Beat Müllhaupt consults and received grants from Gilead and consults for Ipsen. Pierre Nahon consults and received grants from AstraZeneca, Bristol-Myers Squibb, and Eisai. He consults for Ipsen and Roche. Eric Trépo received grants from Gilead and Julius Clinical.

Figures

**FIGURE 1**
Flowchart of cohorts. Flowchart depicting the overall study design and number of participants included in each component. Abbreviations: ALC, alcohol-associated liver cirrhosis; GWAS, Genome-wide Association Study; NIAAA, National Institute on Alcohol Abuse and Alcoholism; PRS, Polygenic Risk Score; R-sq, R-squared.

**FIGURE 2**
Plot of adjusted ORs across 3 cohorts Bar plot of covariates adjusted ORs between the bottom decile (0%–10% group) and each decile of PRSALC in the target and 2 validation cohorts. Abbreviations: ALC, alcohol-associated liver cirrhosis; IB-Liver: Indiana Biobank Liver.

See this image and copyright information in PMC

References

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A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry

Affiliations

A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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