Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis

Jonas Ghouse; Gardar Sveinbjörnsson; Marijana Vujkovic; Anne-Sofie Seidelin; Helene Gellert-Kristensen; Gustav Ahlberg; Vinicius Tragante; Søren A Rand; Joseph Brancale; Silvia Vilarinho; Pia Rengtved Lundegaard; Erik Sørensen; Christian Erikstrup; Mie Topholm Bruun; Bitten Aagaard Jensen; Søren Brunak; Karina Banasik; Henrik Ullum; DBDS Genomic Consortium; Niek Verweij; Luca Lotta; Aris Baras; Regeneron Genetics Center; Tooraj Mirshahi; David J Carey; Geisinger-Regeneron DiscovEHR Collaboration; VA Million Veteran Program; David E Kaplan; Julie Lynch; Timothy Morgan; Tae-Hwi Schwantes-An; Daniel R Dochtermann; Saiju Pyarajan; Philip S Tsao; Estonian Biobank Research Team; Triin Laisk; Reedik Mägi; Julia Kozlitina; Anne Tybjærg-Hansen; David Jones; Kirk U Knowlton; Lincoln Nadauld; Egil Ferkingstad; Einar S Björnsson; Magnus O Ulfarsson; Árni Sturluson; Patrick Sulem; Ole B Pedersen; Sisse R Ostrowski; Daniel F Gudbjartsson; Kari Stefansson; Morten Salling Olesen; Kyong-Mi Chang; Hilma Holm; Henning Bundgaard; Stefan Stender

doi:10.1038/s41588-024-01720-y

Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis

Nat Genet. 2024 Apr 17. doi: 10.1038/s41588-024-01720-y. Online ahead of print.

Authors

Jonas Ghouse^{1

2}, Gardar Sveinbjörnsson³, Marijana Vujkovic^{4

5

6}, Anne-Sofie Seidelin⁷, Helene Gellert-Kristensen⁷, Gustav Ahlberg⁸, Vinicius Tragante³, Søren A Rand^{9

8}, Joseph Brancale¹⁰, Silvia Vilarinho¹⁰, Pia Rengtved Lundegaard⁸, Erik Sørensen¹¹, Christian Erikstrup¹², Mie Topholm Bruun¹³, Bitten Aagaard Jensen¹⁴, Søren Brunak¹⁵, Karina Banasik¹⁶, Henrik Ullum¹⁷; DBDS Genomic Consortium; Niek Verweij¹⁸, Luca Lotta¹⁸, Aris Baras¹⁸; Regeneron Genetics Center; Tooraj Mirshahi¹⁹, David J Carey¹⁹; Geisinger-Regeneron DiscovEHR Collaboration; VA Million Veteran Program; David E Kaplan^{4

5}, Julie Lynch^{20

21}, Timothy Morgan^{22

23}, Tae-Hwi Schwantes-An^{22

24}, Daniel R Dochtermann²⁵, Saiju Pyarajan^{25

26}, Philip S Tsao^{27

28}; Estonian Biobank Research Team; Triin Laisk²⁹, Reedik Mägi²⁹, Julia Kozlitina³⁰, Anne Tybjærg-Hansen⁷, David Jones³¹, Kirk U Knowlton^{32

33}, Lincoln Nadauld^{31

34}, Egil Ferkingstad³, Einar S Björnsson^{35

36}, Magnus O Ulfarsson^{3

37}, Árni Sturluson³, Patrick Sulem³, Ole B Pedersen^{38

39}, Sisse R Ostrowski^{11

38}, Daniel F Gudbjartsson^{3

40}, Kari Stefansson³, Morten Salling Olesen^{9

8}, Kyong-Mi Chang^{4

5}, Hilma Holm³, Henning Bundgaard^{9

38}, Stefan Stender^{41

42}

Collaborator

Luca A Lotta

Affiliations

¹ Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. jonasghouse@gmail.com.
² Cardiac Genetics Group, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. jonasghouse@gmail.com.
³ deCODE Genetics/Amgen, Reykjavik, Iceland.
⁴ Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
⁵ Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁶ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
⁸ Cardiac Genetics Group, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁹ Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁰ Section of Digestive Diseases, Department of Internal Medicine, and Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
¹¹ Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
¹² Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
¹³ Department of Clinical Immunology, Odense University Hospital, Odense, Denmark.
¹⁴ Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.
¹⁵ Translational Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁶ Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark.
¹⁷ Statens Serum Institut, Copenhagen, Denmark.
¹⁸ Regeneron Genetics Center, Regeneron Pharmaceuticals Inc, Tarrytown, NY, USA.
¹⁹ Department of Molecular and Functional Genomics, Geisinger Health System, Danville, PA, USA.
²⁰ VA Informatics and Computing Infrastructure (VINCI), VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
²¹ Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
²² Gastroenterology Section, Veterans Affairs Long Beach Healthcare System, Long Beach, CA, USA.
²³ Department of Medicine, University of California, Irvine, CA, USA.
²⁴ Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA.
²⁵ Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA, USA.
²⁶ Department of Medicine, Brigham Women's Hospital and Harvard Medical School, Boston, MA, USA.
²⁷ Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto, Palo Alto, CA, USA.
²⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
²⁹ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
³⁰ Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.
³¹ Precision Genomics, Intermountain Healthcare, Saint George, UT, USA.
³² Intermountain Medical Center, Intermountain Heart Institute, Salt Lake City, UT, USA.
³³ University of Utah, School of Medicine, Salt Lake City, UT, USA.
³⁴ Stanford University, School of Medicine, Stanford, CA, USA.
³⁵ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
³⁶ Internal Medicine and Emergency Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.
³⁷ Faculty of Electrical and Computer Engineering, University of Iceland, Reykjavik, Iceland.
³⁸ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
³⁹ Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.
⁴⁰ School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
⁴¹ Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. stefan.stender@regionh.dk.
⁴² Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. stefan.stender@regionh.dk.

PMID: 38632349
DOI: 10.1038/s41588-024-01720-y

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.