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, Niek Verweij, Luca LottaAris Baras, Tooraj Mirshahi, David J Carey, David E Kaplan, Julie Lynch, Timothy Morgan, Tae-Hwi Schwantes-An, Daniel R Dochtermann, Saiju Pyarajan, Philip S Tsao, 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, Henning Bundgaard, Stefan Stender*, DBDS Genomic Consortium

*Corresponding author for this work

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.

Original languageEnglish
JournalNature Genetics
Volume56
Issue number5
Pages (from-to)827-837
Number of pages11
ISSN1061-4036
DOIs
Publication statusPublished - May 2024

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