Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis
- PMID: 38632349
- PMCID: PMC11096111
- DOI: 10.1038/s41588-024-01720-y
Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis
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.
© 2024. The Author(s).
Conflict of interest statement
The authors who are affiliated with deCODE genetics/Amgen declare competing financial interests as employees. H.B. receives lecture fees from Bristol-Myers Squibb, Merck Sharp and Dohme. J.G. has received lecture fee from Illumina. S.B. is a board member for Proscion A/S and Intomics A/S. N.V., L.L. and A.B. are employees at Regeneron Genetics Center. All other authors have no conflict of interest to declare.
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