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Circulation
. 2022 Apr 7.
doi: 10.1161/CIRCULATIONAHA.121.057888. Online ahead of print.
Genetic Landscape of the ACE2 Coronavirus Receptor
Zhijian Yang 1 , Erin MacDonald-Dunlop 2 , Jiantao Chen 1 , Ranran Zhai 1 , Ting Li 1 , Anne Richmond 3 , Lucija Klaric 3 , Nicola Pirastu 4 , Zheng Ning 5 , Chenqing Zheng 6 , Yipeng Wang 6 , Tingting Huang 7 , Yazhou He 8 , Huiming Guo 9 , Kejun Ying 10 , Stefan Gustafsson 11 , Bram Prins 12 , Anna Ramisch 13 , Emmanouil T Dermitzakis 13 , Grace Png 14 , Niclas Eriksson 15 , Jeffrey Haessler 16 , Xiaowei Hu 17 , Daniela Zanetti 18 , Thibaud Boutin 3 , Shih-Jen Hwang 19 , Eleanor Wheeler 20 , Maik Pietzner 21 , Laura M Raffield 22 , Anette Kalnapenkis 23 , James E Peters 24 , Ana Viñuela 25 , Arthur Gilly 26 , Sölve Elmståhl 27 , George Dedoussis 28 , John R Petrie 29 , Ozren Polašek 30 , Lasse Folkersen 31 , Yan Chen 7 , Chen Yao 19 , Urmo Võsa 32 , Erola Pairo-Castineira 33 , Sara Clohisey 34 , Andrew D Bretherick 3 , Konrad Rawlik 34 , Tõnu Esko 32 , Stefan Enroth 35 , Åsa Johansson 35 , Ulf Gyllensten 35 , Claudia Langenberg 21 , Daniel Levy 19 , Caroline Hayward 3 , Themistocles L Assimes 18 , Charles Kooperberg 16 , Ani W Manichaikul 17 , Agneta Siegbahn 11 , Lars Wallentin 36 , Lars Lind 11 , Eleftheria Zeggini 37 , Jochen M Schwenk 38 , Adam S Butterworth 39 , Karl Michaëlsson 40 , Yudi Pawitan 7 , Peter K Joshi 2 , J Kenneth Baillie 41 , Anders Mälarstig 42 , Alexander P Reiner 16 , James F Wilson 43 , Xia Shen 44 , GenOMICC Consortium and the IMI-DIRECT Consortium
Affiliations
- PMID: 35387486
- DOI: 10.1161/CIRCULATIONAHA.121.057888
Abstract
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, enters human cells using the angiotensin-converting enzyme 2 (ACE2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart, respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biologic systems. However, the genetic basis of the ACE2 protein levels is not well understood. Methods: We conduct so far the largest genome-wide association meta-analysis of plasma ACE2 levels in over 28,000 individuals of the SCALLOP Consortium. We summarize the cross-sectional epidemiologic 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 disease severity using Mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data. Results: We identified ten loci, including eight novel, capturing 30% of the protein's heritability. 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-pQTL-based Mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio (OR), 1.63; 95% CI, 1.10 to 2.42; P = 0.01), hospitalization (OR, 1.52; 95% CI, 1.05 to 2.21; P = 0.03), and infection (OR, 1.60; 95% CI, 1.08 to 2.37; P = 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.