A multi-ancestry genome-wide association study (GWAS) on liver cirrhosis and its endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase, identified 14 risk variants associated with cirrhosis. These variants are located near genes involved in hepatic lipid metabolism. One variant, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity, and diabetes to increase cirrhosis and hepatocellular carcinoma (HCC) risk. A polygenic risk score (PRS) was developed to predict cirrhosis progression to HCC. Rare coding variants in GPAM were associated with lower ALT levels, suggesting GPAM as a potential therapeutic target. The study also identified 36 risk variants for cirrhosis, including 14 that replicated in an independent cohort. The study found that common and rare variants contribute to cirrhosis risk, with some variants showing stronger effects on cirrhosis than on non-alcoholic fatty liver disease (NAFLD). The PRS was associated with increased cirrhosis risk and HCC progression. The study also identified gene variants associated with liver-related outcomes and found that PRSs could predict cirrhosis risk and progression. The study highlights the genetic architecture of cirrhosis and provides insights into potential therapeutic targets. The findings suggest that understanding the genetic factors underlying cirrhosis can improve prediction, prevention, and treatment of the disease. The study included data from 12 cohorts, with 18,265 cirrhosis cases and 1.8 million controls, and validated results in a separate cohort of 21,689 cases and 617,729 controls. The study also examined interactions between genetic variants and environmental factors such as alcohol consumption, obesity, and type 2 diabetes. The results suggest that genetic and environmental factors interact to influence cirrhosis risk. The study provides a comprehensive understanding of the genetic basis of cirrhosis and its associated conditions.A multi-ancestry genome-wide association study (GWAS) on liver cirrhosis and its endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase, identified 14 risk variants associated with cirrhosis. These variants are located near genes involved in hepatic lipid metabolism. One variant, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity, and diabetes to increase cirrhosis and hepatocellular carcinoma (HCC) risk. A polygenic risk score (PRS) was developed to predict cirrhosis progression to HCC. Rare coding variants in GPAM were associated with lower ALT levels, suggesting GPAM as a potential therapeutic target. The study also identified 36 risk variants for cirrhosis, including 14 that replicated in an independent cohort. The study found that common and rare variants contribute to cirrhosis risk, with some variants showing stronger effects on cirrhosis than on non-alcoholic fatty liver disease (NAFLD). The PRS was associated with increased cirrhosis risk and HCC progression. The study also identified gene variants associated with liver-related outcomes and found that PRSs could predict cirrhosis risk and progression. The study highlights the genetic architecture of cirrhosis and provides insights into potential therapeutic targets. The findings suggest that understanding the genetic factors underlying cirrhosis can improve prediction, prevention, and treatment of the disease. The study included data from 12 cohorts, with 18,265 cirrhosis cases and 1.8 million controls, and validated results in a separate cohort of 21,689 cases and 617,729 controls. The study also examined interactions between genetic variants and environmental factors such as alcohol consumption, obesity, and type 2 diabetes. The results suggest that genetic and environmental factors interact to influence cirrhosis risk. The study provides a comprehensive understanding of the genetic basis of cirrhosis and its associated conditions.