Meta-Analysis

. 2022 May 3;145(18):1398-1411.

doi: 10.1161/CIRCULATIONAHA.121.057888. Epub 2022 Apr 7.

Genetic Landscape of the ACE2 Coronavirus Receptor

Zhijian Yang^#^{1

2}, Erin Macdonald-Dunlop^#³, Jiantao Chen^{1

2}, Ranran Zhai^{1

2}, Ting Li^{1

2}, Anne Richmond⁴, Lucija Klarić⁴, Nicola Pirastu^{3

5}, Zheng Ning^{1

6}, Chenqing Zheng¹, Yipeng Wang¹, Tingting Huang⁶, Yazhou He^{3

7}, Huiming Guo⁸, Kejun Ying^{9

10}, Stefan Gustafsson¹¹, Bram Prins^{12

13}, Anna Ramisch¹⁴, Emmanouil T Dermitzakis¹⁴, Grace Png^{15

16}, Niclas Eriksson¹⁷, Jeffrey Haessler¹⁸, Xiaowei Hu¹⁹, Daniela Zanetti^{20

21}, Thibaud Boutin⁴, Shih-Jen Hwang^{22

23}, Eleanor Wheeler²⁴, Maik Pietzner^{24

25}, Laura M Raffield²⁶, Anette Kalnapenkis^{27

28}, James E Peters^{29

12

13}, Ana Viñuela^{14

30}, Arthur Gilly^{15

31}, Sölve Elmståhl³², George Dedoussis³³, John R Petrie³⁴, Ozren Polašek^{35

36}, Lasse Folkersen³⁷, Yan Chen⁶, Chen Yao^{22

23}, Urmo Võsa²⁷, Erola Pairo-Castineira^{4

38}, Sara Clohisey³⁸, Andrew D Bretherick⁴, Konrad Rawlik³⁸; GenOMICC Consortium†; IMI-DIRECT Consortium†; Tõnu Esko²⁷, Stefan Enroth³⁹, Åsa Johansson³⁹, Ulf Gyllensten³⁹, Claudia Langenberg^{24

25}, Daniel Levy^{22

23}, Caroline Hayward⁴, Themistocles L Assimes^{20

21}, Charles Kooperberg¹⁸, Ani W Manichaikul¹⁹, Agneta Siegbahn¹¹, Lars Wallentin¹¹, Lars Lind¹¹, Eleftheria Zeggini^{15

31

40}, Jochen M Schwenk⁴¹, Adam S Butterworth^{12

13

42

43}, Karl Michaëlsson⁴⁴, Yudi Pawitan⁶, Peter K Joshi³, J Kenneth Baillie^{38

45}, Anders Mälarstig^{6

46}, Alexander P Reiner¹⁸, James F Wilson^#^{3

4}, Xia Shen^#^{1

47

2

3

6}

Affiliations

¹ Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China (Z.Y., J.C., R.Z., T.L., Z.N., C.Z., Y.W., X.S.).
² Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, China (Z.Y., J.C., R.Z., T.L., X.S.).
³ Centre for Global Health Research, Usher Institute, University of Edinburgh, UK (E.M.-D., N.P., Y.H., P.K.J., J.F.W., X.S.).
⁴ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, UK (A. Richmond, L.K., T.B., E.P.-C., A.D.B., C.H., J.F.W.).
⁵ Human Technopole Viale Rita Levi-Montalcini, Milan, Italy (N.P.).
⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (Z.N., T.H., Y.C., Y.P., A.M., X.S.).
⁷ West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu (Y.H.).
⁸ Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences, Guangzhou, China (H.G.).
⁹ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (K.Y.).
¹⁰ T.H. Chan School of Public Health, Harvard University, Boston, MA (K.Y.).
¹¹ Department of Medical Sciences, Uppsala University, Sweden (A.S., S.G., L.W., L.L.).
¹² British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK (B.P., J.E.P., A.S.B.).
¹³ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge (B.P., J.E.P., A.S.B.).
¹⁴ Department of Genetic Medicine and Development, University of Geneva Medical School, Switzerland (A. Ramisch, E.T.D., A.V.).
¹⁵ Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany (G.P., A.G., E.Z.).
¹⁶ Technical University of Munich (TUM), School of Medicine, Germany (G.P.).
¹⁷ Uppsala Clinical Research Center, Sweden (N.E.).
¹⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (J.H., C.K., A.P.R.).
¹⁹ Center for Public Health Genomics, University of Virginia, Charlottesville (X.H., A.W.M.).
²⁰ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (D.Z., T.L.A.).
²¹ Stanford Cardiovascular Institute, Stanford University, CA (D.Z., T.L.A.).
²² Framingham Heart Study, MA (S.-J.H., C.Y., D.L.).
²³ Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (S.-J.H., C.Y., D.L.).
²⁴ MRC Epidemiology Unit, University of Cambridge, UK (E.W., M.P., C.L.).
²⁵ Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin, Germany (M.P., C.L.).
²⁶ Department of Genetics, University of North Carolina at Chapel Hill (L.M.R.).
²⁷ Estonian Genome Centre, Institute of Genomics, University of Tartu, Estonia (A.K., U.V., T.E.).
²⁸ Institute of Molecular and Cell Biology, University of Tartu, Estonia (A.K.).
²⁹ Department of Immunology and Inflammation, Imperial College London, UK (J.E.P.).
³⁰ Biosciences Institute, Faculty of Medical Sciences, Newcastle University, UK (A.V.).
³¹ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK (A.G., E.Z.).
³² Faculty of Medicine, Lund University, Sweden (S. Elmståhl).
³³ Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Greece (G.D.).
³⁴ Institute of Cardiovascular & Medical Sciences, University of Glasgow, UK (J. Petrie).
³⁵ University of Split School of Medicine, Croatia (O.P.).
³⁶ Algebra University College, Ilica, Zagreb, Croatia (O.P.).
³⁷ Danish National Genome Center, Copenhagen, Denmark (L.F.).
³⁸ Roslin Institute, University of Edinburgh, Easter Bush, UK (E.P.-C., S.C., K.R., J.K.B.).
³⁹ Department of Immunology, Genetics and Pathology, Uppsala Universitet, Science for Life Laboratory, Sweden (S. Enroth, A.J., U.G.).
⁴⁰ Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine, Germany (E.Z.).
⁴¹ Affinity Proteomics, Science for Life Laboratory, KTH Royal Institute of Technology, Solna, Sweden (J.M.S.).
⁴² British Heart Foundation Centre of Research Excellence, University of Cambridge, UK (A.S.B.).
⁴³ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, UK (A.S.B.).
⁴⁴ Department of Surgical Sciences, Uppsala University, Sweden (K.M.).
⁴⁵ Intensive Care Unit, Royal Infirmary of Edinburgh, UK (J.K.B.).
⁴⁶ Pfizer Worldwide Research, Development and Medical, Stockholm, Sweden (A.M.).
⁴⁷ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China (X.S.).

^# Contributed equally.

PMID: 35387486
PMCID: PMC9047645
DOI: 10.1161/CIRCULATIONAHA.121.057888

Meta-Analysis

Genetic Landscape of the ACE2 Coronavirus Receptor

Zhijian Yang et al. Circulation. 2022.

. 2022 May 3;145(18):1398-1411.

doi: 10.1161/CIRCULATIONAHA.121.057888. Epub 2022 Apr 7.

Authors

Affiliations

¹ Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China (Z.Y., J.C., R.Z., T.L., Z.N., C.Z., Y.W., X.S.).
² Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, China (Z.Y., J.C., R.Z., T.L., X.S.).
³ Centre for Global Health Research, Usher Institute, University of Edinburgh, UK (E.M.-D., N.P., Y.H., P.K.J., J.F.W., X.S.).
⁴ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, UK (A. Richmond, L.K., T.B., E.P.-C., A.D.B., C.H., J.F.W.).
⁵ Human Technopole Viale Rita Levi-Montalcini, Milan, Italy (N.P.).
⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (Z.N., T.H., Y.C., Y.P., A.M., X.S.).
⁷ West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu (Y.H.).
⁸ Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences, Guangzhou, China (H.G.).
⁹ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (K.Y.).
¹⁰ T.H. Chan School of Public Health, Harvard University, Boston, MA (K.Y.).
¹¹ Department of Medical Sciences, Uppsala University, Sweden (A.S., S.G., L.W., L.L.).
¹² British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK (B.P., J.E.P., A.S.B.).
¹³ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge (B.P., J.E.P., A.S.B.).
¹⁴ Department of Genetic Medicine and Development, University of Geneva Medical School, Switzerland (A. Ramisch, E.T.D., A.V.).
¹⁵ Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany (G.P., A.G., E.Z.).
¹⁶ Technical University of Munich (TUM), School of Medicine, Germany (G.P.).
¹⁷ Uppsala Clinical Research Center, Sweden (N.E.).
¹⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (J.H., C.K., A.P.R.).
¹⁹ Center for Public Health Genomics, University of Virginia, Charlottesville (X.H., A.W.M.).
²⁰ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (D.Z., T.L.A.).
²¹ Stanford Cardiovascular Institute, Stanford University, CA (D.Z., T.L.A.).
²² Framingham Heart Study, MA (S.-J.H., C.Y., D.L.).
²³ Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (S.-J.H., C.Y., D.L.).
²⁴ MRC Epidemiology Unit, University of Cambridge, UK (E.W., M.P., C.L.).
²⁵ Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin, Germany (M.P., C.L.).
²⁶ Department of Genetics, University of North Carolina at Chapel Hill (L.M.R.).
²⁷ Estonian Genome Centre, Institute of Genomics, University of Tartu, Estonia (A.K., U.V., T.E.).
²⁸ Institute of Molecular and Cell Biology, University of Tartu, Estonia (A.K.).
²⁹ Department of Immunology and Inflammation, Imperial College London, UK (J.E.P.).
³⁰ Biosciences Institute, Faculty of Medical Sciences, Newcastle University, UK (A.V.).
³¹ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK (A.G., E.Z.).
³² Faculty of Medicine, Lund University, Sweden (S. Elmståhl).
³³ Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Greece (G.D.).
³⁴ Institute of Cardiovascular & Medical Sciences, University of Glasgow, UK (J. Petrie).
³⁵ University of Split School of Medicine, Croatia (O.P.).
³⁶ Algebra University College, Ilica, Zagreb, Croatia (O.P.).
³⁷ Danish National Genome Center, Copenhagen, Denmark (L.F.).
³⁸ Roslin Institute, University of Edinburgh, Easter Bush, UK (E.P.-C., S.C., K.R., J.K.B.).
³⁹ Department of Immunology, Genetics and Pathology, Uppsala Universitet, Science for Life Laboratory, Sweden (S. Enroth, A.J., U.G.).
⁴⁰ Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine, Germany (E.Z.).
⁴¹ Affinity Proteomics, Science for Life Laboratory, KTH Royal Institute of Technology, Solna, Sweden (J.M.S.).
⁴² British Heart Foundation Centre of Research Excellence, University of Cambridge, UK (A.S.B.).
⁴³ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, UK (A.S.B.).
⁴⁴ Department of Surgical Sciences, Uppsala University, Sweden (K.M.).
⁴⁵ Intensive Care Unit, Royal Infirmary of Edinburgh, UK (J.K.B.).
⁴⁶ Pfizer Worldwide Research, Development and Medical, Stockholm, Sweden (A.M.).
⁴⁷ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China (X.S.).

^# Contributed equally.

PMID: 35387486
PMCID: PMC9047645
DOI: 10.1161/CIRCULATIONAHA.121.057888

Erratum in

Correction to: Genetic Landscape of the ACE2 Coronavirus Receptor.
[No authors listed] [No authors listed] Circulation. 2022 Jul 5;146(1):e4. doi: 10.1161/CIR.0000000000001081. Epub 2022 Jul 5. Circulation. 2022. PMID: 35858169 Free PMC article. No abstract available.

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 >28 000 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]; P=0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05-2.21]; P=0.03), and infection (odds ratio, 1.60 [95% CI, 1.08-2.37]; 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.

Keywords: COVID-19; Genome-Wide Association Study; SARS-CoV-2; angiotensin-converting enzyme 2; cardiovascular diseases.

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Figures

**Figure 1.**
**Genomic meta-analysis scan of plasma ACE2.** Mapped genes are labeled at genome-wide significant loci (P<5×10⁻⁸). Genome-wide significant variants with minor allele frequency <0.05 are marked as circles instead of solid dots. Illustrations are provided for the interactions between 2 pairs of mapped loci; the locus on chromosome 16 is a transcription binding site for the transcription factor HNF4A mapped on chromosome 20, and HNF1A acts as the transcription factor for the *ACE2* gene. ACE2 indicates angiotensin-converting enzyme 2; and TFBS, transcription factor binding site.

**Figure 2.**
**Genetic correlations between plasma ACE2 and human complex traits and diseases. A**, Statistically significant (false discovery rate <5%) genetic correlations with ACE2 (angiotensin-converting enzyme 2) are shown; severe COVID-19, C-reactive protein (CRP), and other representative traits are labeled. Error bars represent SEs. Colors label different groups of phenotypes. Detailed explanations of the annotated phenotypes are given in the Supplemental Material. B, Enrichment of genetic correlations with ACE2 within each group of phenotypes. Circles are the quantile-quantile (QQ) plots of the genetic correlations test statistics against the null, whereas the solid dots are the QQ plots of the test statistics within each phenotype group against all the analyzed phenotypes. BMI indicates body mass index; FVC, forced vital capacity; and SBP, systolic blood pressure.

**Figure 3.**
**Genetic and causal relationships between plasma ACE2 and vascular diseases.** Estimates significantly different from zero are highlighted in filled circles. First 2 forest plots show the bidirectional generalized summary-level mendelian randomization (GSMR) analysis results between plasma ACE2 (angiotensin-converting enzyme 2) and 48 vascular disease–related traits. Third forest plot gives the corresponding genetic correlations estimates between plasma ACE2 and these phenotypes. Last forest plot shows the estimated mendelian randomization (MR) effects based on cis–protein quantitative trait loci (pQTL) only. HDL indicates high-density lipoprotein; LDL, low-density lipoprotein; OR, odds ratio; and SAH, subarachnoid hemorrhage.

**Figure 4.**
**Causal inference between plasma ACE2 and COVID-19 based on the *ACE2* cis-pQTL. A**, The regional genome-wide association study z scores across 4 traits are compared; alleles are coded so that the estimated single nucleotide polymorphism (SNP) effects on ACE2 (angiotensin-converting enzyme 2) are all positive. Genome-wide significant SNPs for ACE2 (P<5×10⁻⁸) are highlighted in yellow. The 3 SNPs representing independent significant associations after linkage disequilibrium (LD) clumping (r²<0.001) are marked in red. B, Inference of the causal effect of ACE2 on COVID-19 through mendelian randomization (MR). The MR was performed with an inverse-variance weighted causal effect estimator based on multiple genome-wide significant cis-regulatory SNPs. A threshold of R²<0.001 was applied to prune out SNPs in LD. Whiskers represent 95% CIs. OR indicates odds ratio.

See this image and copyright information in PMC

References

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Genetic Landscape of the ACE2 Coronavirus Receptor

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Genetic Landscape of the ACE2 Coronavirus Receptor

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