近日，丹麦哥本哈根大学Stefan Stender等研究人员合作发现，常见变异和罕见变异的整合分析有助于深入了解肝硬化的遗传结构。2024年4月17日，《自然—遗传学》杂志在线发表了这项成果。

研究人员报告了一项关于肝硬化及其相关内表型，即丙氨酸氨基转移酶（ALT）和γ-谷氨酰转移酶，的多队列全基因组关联研究。利用来自12个队列的数据，包括18265例肝硬化病例、1782047例对照、多达100万例肝功能检测者以及21689例病例和617729例对照的验证队列，研究人员确定并验证了14种肝硬化风险关联。许多变异位于涉及肝脏脂质代谢的基因附近。其中，PNPLA3p.Ile148Met与酒精摄入、肥胖和糖尿病对肝硬化和肝细胞癌（HCC）的风险有相互作用。

研究人员制定了一个多基因风险评分，该评分与肝硬化发展为HCC的过程相关。通过关注常见变异分析中的优先基因，研究人员发现GPAM中的罕见编码变异与较低的ALT有关，支持将GPAM作为治疗抑制的潜在靶点。总之，本研究为肝硬化的遗传基础提供了深入见解。

附：英文原文

Title: Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis

Author: Ghouse, Jonas, Sveinbjrnsson, Gardar, Vujkovic, Marijana, Seidelin, Anne-Sofie, Gellert-Kristensen, Helene, Ahlberg, Gustav, Tragante, Vinicius, Rand, Sren A., Brancale, Joseph, Vilarinho, Silvia, Lundegaard, Pia Rengtved, Srensen, Erik, Erikstrup, Christian, Bruun, Mie Topholm, Jensen, Bitten Aagaard, Brunak, Sren, 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, Mgi, Reedik, Kozlitina, Julia, Tybjrg-Hansen, Anne, Jones, David, Knowlton, Kirk U., Nadauld, Lincoln, Ferkingstad, Egil, Bjrnsson, Einar S., Ulfarsson, Magnus O., Sturluson, rni, 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

Issue&Volume: 2024-04-17

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.

DOI: 10.1038/s41588-024-01720-y

Source: https://www.nature.com/articles/s41588-024-01720-y