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.

我们报告了一项关于肝硬化及其相关内表型、丙氨酸氨基转移酶（ALT）和γ-谷氨酰转移酶的多祖先全基因组关联研究。利用来自 12 个队列的数据，包括 18,265 例肝硬化病例、1,782,047 名对照者、多达 100 万名接受肝功能检测的个体以及由 21,689 例病例和 617,729 名对照者组成的验证队列，我们​​识别并验证了 14 个与肝硬化的风险关联。许多变异位于参与肝脏脂质代谢的基因附近。其中之一，PNPLA3 p.Ile148Met，与酒精摄入、肥胖和糖尿病相互作用，增加肝硬化和肝细胞癌 (HCC) 的风险。我们开发了一个与从肝硬化到肝癌进展相关的多基因风险评分。通过关注常见变异分析中的优先基因，我们发现GPAM中罕见的编码变异与较低的 ALT 相关，支持GPAM作为治疗抑制的潜在靶点。总之，这项研究提供了对肝硬化遗传基础的见解。