학술논문
Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis
Document Type
Original Paper
Author
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; Stender, Stefan
Source
Nature Genetics. 56(5):827-837
Subject
Language
English
ISSN
1061-4036
1546-1718
1546-1718
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.
A multi-ancestry genome-wide association study of liver cirrhosis and its associated endophenotypes identifies and validates 14 risk variants. Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.
A multi-ancestry genome-wide association study of liver cirrhosis and its associated endophenotypes identifies and validates 14 risk variants. Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.