Lineage-specific positive selection on ACE2 contributes to the genetic susceptibility of COVID-19

作     者：Yuwen Pan Panhong Liu Fang Wang Peng Wu Fanjun Cheng Xin Jin Shuhua Xu 

作者机构：Key Laboratory of Computational Biology Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences College of Life Sciences University of Chinese Academy of Sciences The Third People’s Hospital of Shenzhen National Clinical Research Center for Infectious Disease The Second Affiliated Hospital of Southern University of Science and Technology Cancer Biology Research Center (Key Laboratory of the Ministry of Education) Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Department of Gynecologic Oncology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Department of Hematology Union Hospital Tongji Medical College Huazhong University of Science and Technology School of Medicine South China University of Technology Department of Liver Surgery and Transplantation Liver Cancer Institute Zhongshan Hospital Fudan University State Key Laboratory of Genetic Engineering Collaborative Innovation Center of Genetics and Development Center for Evolutionary Biology School of Life Sciences Fudan University Human Phenome Institute Zhangjiang Fudan International Innovation Center and Ministry of Education Key Laboratory of Contemporary Anthropology Fudan University School of Life Science and Technology ShanghaiTech University Center for Excellence in Animal Evolution and Genetics Chinese Academy of Sciences 

出 版 物：《National Science Review》 (国家科学评论(英文版))

年 卷 期：2022年第9卷第9期

页      面：155-165页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China (NSFC)(32041008, 32030020, 32000398and 31961130380) the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS)(XDPB17 and XDB38000000) the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01) the Natural Science Foundation of Guangdong Province China (2017A030306026) the Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases (2019B121205005) 

主　　题：ACE2 COVID-19 genetic susceptibility genetic diversity natural selection East Asia 

摘      要：The Angiotensin-Converting Enzyme-2(ACE2) gene,located on Xp22.2, attracts a great deal of attention because the protein it encodes is believed to be the functional cellular receptor for the new coronavirus(SARS-CoV-2).However,recent studies are controversial,especially concerning the intrinsic link between ACE2 diversity and COVID-19 ***,we conduct a population genetic study on ACE2 in6354 individuals representing 210 present-day populations and 5 329 individuals of ancient or archaic *** dissected the genetic architecture ofACE2 and identified two major haplogroups(hg) in East Asians,***2-hgl(43%) and ACE2-hg2(53%),while other populations harbor more diverse A ***,there was a significant loss of ACE2 common variations in East Asians in contrast to the X-chromosome-wide and genome-wide ***,association analysis between ACE2-hgs and COVID-19 severity in 1229 Han Chinese individuals with various levels of COVID-19 severity showed a higher risk ofACE2-hgl(odds ratio=1.56,P 0.01) and a lower risk of ACE2-hg2(odds ratio=0.65,P 0.01).Interestingly,ACE2-hgl is in strong linkage disequilibrium with rs1849863-C,which is an assumed risk factor of elevated plasma ACE2 level and is related to a higher risk of COVID-19 severity,hospitalization and ***,remarkable signatures of positive selection were detected,especially on ACE2-hg2,and were traced back to 100 000 years ago(but rose to a strong level during the Bronze Age,5000～3000 years ago,in East Asians).The selection pressures could have stemmed from multiple sources,but pre-COVID-19 viral epidemics and pandemics might have been potential driving forces,which consequently contributed to the genetic susceptibility to COVID-19 within and between populations.