Genetic Landscape of the ACE2 Coronavirus Receptor

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.

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UNC Libraries
Published
2025-04-16
DOI
https://doi.org/10.17615/ryg7-6f72
Primary Topic
SARS-CoV-2 and COVID-19 Research
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article
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article

Genetic Landscape of the ACE2 Coronavirus Receptor

Huiming Guo, Daniel L. Levy, Anette Kalnapenkis, Tōnu Esko et al.
UNC Libraries
SARS-CoV-2 and COVID-19 Research
article

Genetic Landscape of the ACE2 Coronavirus Receptor

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

Abstract

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.

UNC Libraries
University of North Carolina at Chapel Hill (US)
Openalex Percentile: Top 65%
SARS-CoV-2 and COVID-19 Research
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