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

Pan, Yuwen1; Liu, Panhong8; Wang, Fang9; Wu, Peng10,11; Cheng, Fanjun12; Jin, Xin13; Xu, Shuhua2,3,4,5,6,7

2022-10-03

10.1093/nsr/nwac118

National Science Review   Impact Factor & Quartile

2095-5138

2053-714X

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 susceptibility. Here, we conduct a population genetic study on ACE2 in 6354 individuals representing 210 present-day populations and 5329 individuals of ancient or archaic groups. We dissected the genetic architecture of ACE2 and identified two major haplogroups (hg) in East Asians, i.e. ACE2-hg1 (43%) and ACE2-hg2 (53%), while other populations harbor more diverse ACE2-hgs. Accordingly, there was a significant loss of ACE2 common variations in East Asians in contrast to the X-chromosome-wide and genome-wide patterns. Notably, 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 of ACE2-hg1 (odds ratio = 1.56, P < 0.01) and a lower risk of ACE2-hg2 (odds ratio = 0.65, P < 0.01). Interestingly, ACE2-hg1 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 infection. Strikingly, 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 similar to 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.

ACE2 COVID-19 genetic susceptibility genetic diversity natural selection East Asia

SCI

English

Others

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

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:000863742800002

OXFORD UNIV PRESS

Web of Science

1.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Key Lab Computat Biol, Shanghai 200031, Peoples R China
2.Fudan Univ, Zhongshan Hosp, Dept Liver Surg & Transplantat Liver Canc Inst, Shanghai 200032, Peoples R China
3.FudanUniv, Ctr Evolutionary Biol, Collaborat Innovat Ctr Genet & Dev, Sch Life Sci,State Key Lab Genet Engn, Shanghai 200433, Peoples R China
4.Fudan Univ, Zhangjiang Fudan Int Innovat Ctr, Human Phenome Inst, Shanghai 201203, Peoples R China
5.Fudan Univ, Key Lab Contemporary Anthropol, Minist Educ, Shanghai 201203, Peoples R China
6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
7.Chinese Acad Sci, Ctr Excellence Anim Evolut & Genet, Kunming 650223, Yunnan, Peoples R China
8.Univ Chinese Acad Sci, Coll Life Sci, Beijing 100049, Peoples R China
9.Southern Univ Sci & Technol, Peoples Hosp Shenzhen 3, Natl Clin Res Ctr Infect Dis, Affiliated Hosp 2, Shenzhen 518112, Peoples R China
10.Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Canc Biol Res Ctr,Key Lab Minist Educ, Wuhan 430030, Peoples R China
11.Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Gynecol Oncol, Wuhan 430030, Peoples R China
12.Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Hematol, Wuhan 430022, Peoples R China
13.South China Univ Technol, Sch Med, Guangzhou 510640, Peoples R China

Pan, Yuwen,Liu, Panhong,Wang, Fang,et al. Lineage-specific positive selection on ACE2 contributes to the genetic susceptibility of COVID-19[J]. National Science Review,2022,9(9).

Pan, Yuwen.,Liu, Panhong.,Wang, Fang.,Wu, Peng.,Cheng, Fanjun.,...&Xu, Shuhua.(2022).Lineage-specific positive selection on ACE2 contributes to the genetic susceptibility of COVID-19.National Science Review,9(9).

Pan, Yuwen,et al."Lineage-specific positive selection on ACE2 contributes to the genetic susceptibility of COVID-19".National Science Review 9.9(2022).