Shi Xiaoqiang, Wang Yan, Yang Zhongli, Yuan Wenji, Li Ming D
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
Research Center for Air Pollution and Health, Zhejiang University, Hangzhou 310058, China.
iScience. 2024 Sep 16;27(10):110976. doi: 10.1016/j.isci.2024.110976. eCollection 2024 Oct 18.
Alcohol dependence is a heritable disorder, yet its genetic basis and underlying mechanisms remain poorly understood, especially in Chinese population. In this study, we conducted gene-based and transcript-based association tests and found a significant association between expression in the cortex and hippocampus of the brain and alcohol use in a cohort of 1,329 individuals with Chinese ancestry. Further analysis using the effective-median-based Mendelian randomization framework for inferring the causal genes (EMIC) revealed a causal relationship between expression in the frontal cortex and alcohol use. Moreover, leveraging extensive European alcohol dependence data, our gene association tests and EMIC analysis showed that expression in the nucleus accumbens was significantly associated with alcohol dependence. Finally, animal studies indicated that knockout mice lacked conditioned place preference for alcohol. Together, our combined human genetic and animal studies indicate that plays a crucial role in alcohol dependence.
酒精依赖是一种遗传性疾病，但其遗传基础和潜在机制仍知之甚少，尤其是在中国人群中。在本研究中，我们进行了基于基因和转录本的关联测试，发现在1329名具有中国血统的个体队列中，大脑皮层和海马体中的表达与酒精使用之间存在显著关联。使用基于有效中位数的孟德尔随机化框架来推断因果基因（EMIC）的进一步分析揭示了额叶皮层中的表达与酒精使用之间的因果关系。此外，利用大量欧洲酒精依赖数据，我们的基因关联测试和EMIC分析表明，伏隔核中的表达与酒精依赖显著相关。最后，动物研究表明，基因敲除小鼠对酒精缺乏条件性位置偏好。总之，我们结合人类遗传学和动物研究表明，该基因在酒精依赖中起关键作用。
