作者
Jonas Ghouse,Garðar Sveinbjörnsson,Marijana Vujkovic,Anne-Sofie Seidelin,Helene Gellert‐Kristensen,Gustav Ahlberg,Vinicius Tragante,Søren A. Rand,Joseph Brancale,Sílvia Vilarinho,Pia R. Lundegaard,Erik Sørensen,Christian Erikstrup,Mie Topholm Bruun,Bitten Aagaard Jensen,Søren Brunak,Karina Banasik,Henrik Ullum,Niek Verweij,Luca A. Lotta,Aris Baras,Luca A. Lotta,Tooraj Mirshahi,David J. Carey,David E. Kaplan,Julie Lynch,Timothy R. Morgan,Tae‐Hwi Schwantes‐An,Daniel Dochtermann,Saiju Pyarajan,Philip S. Tsao,Triin Laisk,Reedik Mägi,Julia Kozlitina,Anne Tybjærg‐Hansen,David A. Jones,Kirk U. Knowlton,Lincoln Nadauld,Egil Ferkingstad,Einar Björnsson,Magnus Ö. Ulfarsson,Árni Sturluson,Patrick Sulem,Ole Birger Pedersen,Sisse Rye Ostrowski,Daníel F. Guðbjartsson,Kāri Stefánsson,Morten S. Olesen,Kyong‐Mi Chang,Hilma Hólm,Henning Bundgaard,Stefan Stender
摘要
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.