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Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.
Ghouse, Jonas; Sveinbjörnsson, Gardar; Vujkovic, Marijana; Seidelin, Anne-Sofie; Gellert-Kristensen, Helene; Ahlberg, Gustav; Tragante, Vinicius; Rand, Søren A; Brancale, Joseph; Vilarinho, Silvia; Lundegaard, Pia Rengtved; Sørensen, Erik; Erikstrup, Christian; Bruun, Mie Topholm; Jensen, Bitten Aagaard; Brunak, Søren; Banasik, Karina; Ullum, Henrik; Verweij, Niek; Lotta, Luca; Baras, Aris; Mirshahi, Tooraj; Carey, David J; Kaplan, David E; Lynch, Julie; Morgan, Timothy; Schwantes-An, Tae-Hwi; Dochtermann, Daniel R; Pyarajan, Saiju; Tsao, Philip S; Laisk, Triin; Mägi, Reedik; Kozlitina, Julia; Tybjærg-Hansen, Anne; Jones, David; Knowlton, Kirk U; Nadauld, Lincoln; Ferkingstad, Egil; Björnsson, Einar S; Ulfarsson, Magnus O; Sturluson, Árni; Sulem, Patrick; Pedersen, Ole B; Ostrowski, Sisse R; Gudbjartsson, Daniel F; Stefansson, Kari; Olesen, Morten Salling; Chang, Kyong-Mi; Holm, Hilma; Bundgaard, Henning.
Afiliación
  • Ghouse J; Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. jonasghouse@gmail.com.
  • Sveinbjörnsson G; Cardiac Genetics Group, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. jonasghouse@gmail.com.
  • Vujkovic M; deCODE Genetics/Amgen, Reykjavik, Iceland.
  • Seidelin AS; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
  • Gellert-Kristensen H; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • Ahlberg G; Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Tragante V; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Rand SA; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Brancale J; Cardiac Genetics Group, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Vilarinho S; deCODE Genetics/Amgen, Reykjavik, Iceland.
  • Lundegaard PR; Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Sørensen E; Cardiac Genetics Group, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Erikstrup C; Section of Digestive Diseases, Department of Internal Medicine, and Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
  • Bruun MT; Section of Digestive Diseases, Department of Internal Medicine, and Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
  • Jensen BA; Cardiac Genetics Group, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Brunak S; Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Banasik K; Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
  • Ullum H; Department of Clinical Immunology, Odense University Hospital, Odense, Denmark.
  • Verweij N; Translational Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Lotta L; Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark.
  • Baras A; Statens Serum Institut, Copenhagen, Denmark.
  • Mirshahi T; Regeneron Genetics Center, Regeneron Pharmaceuticals Inc, Tarrytown, NY, USA.
  • Carey DJ; Regeneron Genetics Center, Regeneron Pharmaceuticals Inc, Tarrytown, NY, USA.
  • Kaplan DE; Department of Molecular and Functional Genomics, Geisinger Health System, Danville, PA, USA.
  • Lynch J; Department of Molecular and Functional Genomics, Geisinger Health System, Danville, PA, USA.
  • Dochtermann DR; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
  • Pyarajan S; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • Tsao PS; VA Informatics and Computing Infrastructure (VINCI), VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
  • Laisk T; Gastroenterology Section, Veterans Affairs Long Beach Healthcare System, Long Beach, CA, USA.
  • Mägi R; Department of Medicine, University of California, Irvine, CA, USA.
  • Kozlitina J; Gastroenterology Section, Veterans Affairs Long Beach Healthcare System, Long Beach, CA, USA.
  • Tybjærg-Hansen A; Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA.
  • Jones D; Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA, USA.
  • Knowlton KU; Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA, USA.
  • Nadauld L; Department of Medicine, Brigham Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Ferkingstad E; Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto, Palo Alto, CA, USA.
  • Björnsson ES; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • Sturluson Á; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
  • Sulem P; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
  • Pedersen OB; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Ostrowski SR; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Gudbjartsson DF; Precision Genomics, Intermountain Healthcare, Saint George, UT, USA.
  • Stefansson K; Intermountain Medical Center, Intermountain Heart Institute, Salt Lake City, UT, USA.
  • Olesen MS; University of Utah, School of Medicine, Salt Lake City, UT, USA.
  • Chang KM; Precision Genomics, Intermountain Healthcare, Saint George, UT, USA.
  • Holm H; Stanford University, School of Medicine, Stanford, CA, USA.
  • Bundgaard H; deCODE Genetics/Amgen, Reykjavik, Iceland.
Nat Genet ; 56(5): 827-837, 2024 May.
Article en En | MEDLINE | ID: mdl-38632349
ABSTRACT
We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Predisposición Genética a la Enfermedad / Estudio de Asociación del Genoma Completo / Cirrosis Hepática Límite: Female / Humans / Male Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2024 Tipo del documento: Article País de afiliación: Dinamarca
Texto completo
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Predisposición Genética a la Enfermedad / Estudio de Asociación del Genoma Completo / Cirrosis Hepática Límite: Female / Humans / Male Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2024 Tipo del documento: Article País de afiliación: Dinamarca