Genetic Landscape of the ACE2 Coronavirus Receptor
Creators: name: Lind, Lars
name: Ying, Kejun
name: Raffield, Laura M.
name: Macdonald-Dunlop, Erin
name: Bretherick, Andrew D.
name: Ramisch, Anna
name: Elmståhl, Sölve
name: Rawlik, Konrad
name: Li, Ting
name: Hu, Xiaowei
name: Klarić, Lucija
name: Petrie, John R.
name: Clohisey, Sara
name: Viñuela, Ana
name: Polašek, Ozren
name: Wang, Yipeng
name: Hwang, Shih-Jen
name: Gyllensten, Ulf
name: Joshi, Peter K.
name: Schwenk, Jochen M.
name: He, Yazhou
name: Guo, Huiming
name: Johansson, Åsa
name: Esko, Tõnu
name: Michaëlsson, Karl
name: Mälarstig, Anders
name: Assimes, Themistocles L.
name: Gustafsson, Stefan
name: Chen, Jiantao
name: Haessler, Jeffrey
name: Dedoussis, George
name: Ning, Zheng
name: Boutin, Thibaud
name: Yao, Chen
name: Wheeler, Eleanor
name: Zanetti, Daniela
name: Butterworth, Adam S.
name: Wallentin, Lars
name: Hayward, Caroline
name: Pirastu, Nicola
name: Gilly, Arthur
name: Yang, Zhijian
name: Eriksson, Niclas
name: Folkersen, Lasse
name: Pietzner, Maik
name: Chen, Yan
name: Enroth, Stefan
name: Zhai, Ranran
name: Huang, Tingting
name: Richmond, Anne
name: Langenberg, Claudia
name: Baillie, J. Kenneth
name: Kalnapenkis, Anette
name: Manichaikul, Ani W.
name: Võsa, Urmo
name: Kooperberg, Charles
name: Peters, James E.
name: Pairo-Castineira, Erola
name: Prins, Bram
name: Zeggini, Eleftheria
name: Pawitan, Yudi
name: Reiner, Alexander P.
name: Zheng, Chenqing
name: Wilson, James F.
name: Dermitzakis, Emmanouil T.
name: Shen, Xia
name: Levy, Daniel
name: Png, Grace
name: Siegbahn, Agneta
Publisher: name: Wolters Kluwer
Year: 2022

description: <p>BACKGROUND: SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood. METHODS: We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in &gt;28&thinsp;000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological correlates of circulating ACE2. Using the summary statistics-based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data. RESULTS: We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis-protein quantitative trait loci-based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10-2.42]; <em>P</em>=0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05-2.21]; <em>P</em>=0.03), and infection (odds ratio, 1.60 [95% CI, 1.08-2.37]; <em>P</em>=0.02). Tissue- and cell type-specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells. CONCLUSIONS: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.</p>