TY - JOUR
T1 - Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis
AU - DBDS Genomic Consortium
AU - Regeneron Genetics Center
AU - Geisinger-Regeneron DiscovEHR Collaboration
AU - VA Million Veteran Program
AU - Estonian Biobank Research Team
AU - Ghouse, Jonas
AU - Sveinbjörnsson, Gardar
AU - Vujkovic, Marijana
AU - Seidelin, Anne Sofie
AU - Gellert-Kristensen, Helene
AU - Ahlberg, Gustav
AU - Tragante, Vinicius
AU - Rand, Søren A.
AU - Brancale, Joseph
AU - Vilarinho, Silvia
AU - Lundegaard, Pia Rengtved
AU - Sørensen, Erik
AU - Erikstrup, Christian
AU - Bruun, Mie Topholm
AU - Jensen, Bitten Aagaard
AU - Brunak, Søren
AU - Banasik, Karina
AU - Ullum, Henrik
AU - Verweij, Niek
AU - Lotta, Luca
AU - Baras, Aris
AU - Mirshahi, Tooraj
AU - Carey, David J.
AU - Kaplan, David E.
AU - Lynch, Julie
AU - Morgan, Timothy
AU - Schwantes-An, Tae Hwi
AU - Dochtermann, Daniel R.
AU - Pyarajan, Saiju
AU - Tsao, Philip S.
AU - Laisk, Triin
AU - Mägi, Reedik
AU - Kozlitina, Julia
AU - Tybjærg-Hansen, Anne
AU - Jones, David
AU - Knowlton, Kirk U.
AU - Nadauld, Lincoln
AU - Ferkingstad, Egil
AU - Björnsson, Einar S.
AU - Ulfarsson, Magnus O.
AU - Sturluson, Árni
AU - Sulem, Patrick
AU - Pedersen, Ole B.
AU - Ostrowski, Sisse R.
AU - Gudbjartsson, Daniel F.
AU - Stefansson, Kari
AU - Olesen, Morten Salling
AU - Chang, Kyong Mi
AU - Holm, Hilma
AU - Bundgaard, Henning
N1 - Publisher Copyright:
© 2024. The Author(s).
PY - 2024/5/1
Y1 - 2024/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85193457668&partnerID=8YFLogxK
U2 - 10.1038/s41588-024-01720-y
DO - 10.1038/s41588-024-01720-y
M3 - Article
C2 - 38632349
AN - SCOPUS:85193457668
SN - 1061-4036
VL - 56
SP - 827
EP - 837
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -