机构：[1]Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China[2]Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, China[3]Centre for Global Health Research, Usher Institute, University of Edinburgh, UK[4]MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, UK[5]Human Technopole Viale Rita Levi-Montalcini, Milan, Italy[6]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden[7]West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu[8]Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences, Guangzhou, China .广东省人民医院[9]Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA[10]T.H. Chan School of Public Health, Harvard University, Boston, MA[11]Department of Medical Sciences, Uppsala University, Sweden[12]British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK[13]Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge[14]Department of Genetic Medicine and Development, University of Geneva Medical School, Switzerland[15]Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany[16]Technical University of Munich (TUM), School of Medicine, Germany[17]Uppsala Clinical Research Center, Sweden[18]Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA[19]Center for Public Health Genomics, University of Virginia, Charlottesville[20]Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, CA[21]Stanford Cardiovascular Institute, Stanford University, CA[22]Framingham Heart Study, MA[23]Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD[24]MRC Epidemiology Unit, University of Cambridge, UK L.[25]Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin, Germany[26]Department of Genetics, University of North Carolina at Chapel Hill[27]Estonian Genome Centre, Institute of Genomics, University of Tartu, Estonia[28]Institute of Molecular and Cell Biology, University of Tartu, Estonia[29]Department of Immunology and Inflammation, Imperial College London, UK[30]Biosciences Institute, Faculty of Medical Sciences, Newcastle University, UK[31]Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK[32]Faculty of Medicine, Lund University, Sweden[33]Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Greece[34]Institute of Cardiovascular & Medical Sciences, University of Glasgow, UK[35]University of Split School of Medicine, Croatia[36]Algebra University College, Ilica, Zagreb, Croatia[37]Danish National Genome Center, Copenhagen, Denmark[38]Roslin Institute, University of Edinburgh, Easter Bush, UK[39]Department of Immunology, Genetics and Pathology, Uppsala Universitet, Science for Life Laboratory, Sweden[40]Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine, Germany[41]Affinity Proteomics, Science for Life Laboratory, KTH Royal Institute of Technology, Solna, Sweden[42]British Heart Foundation Centre of Research Excellence, University of Cambridge, UK[43]National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, UK[44]Department of Surgical Sciences, Uppsala University, Sweden[45]Intensive Care Unit, Royal Infirmary of Edinburgh, UK[46]Pfizer Worldwide Research, Development and Medical, Stockholm, Sweden[47]State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
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.
基金：
Dr Shen received a Swedish Research Council Starting Grant (No. 2017-02543)
and National Natural Science Foundation of China grant (No. 12171495). Drs Wilson
and Hayward acknowledge support from the Medical Research Council Human
Genetics Unit program grant “Quantitative Traits in Health and Disease” (U.
MC_UU_00007/10). The work of Dr Klaric was supported by an RCUK Innovation
Fellowship from the National Productivity Investment Fund (MR/R026408/1). Drs
Zanetti, Petrie, and Assimes were supported by grant R01DK114183. Dr Bretherick
acknowledges funding from the Wellcome PhD training fellowship for clinicians
(204979/Z/16/Z), the Edinburgh Clinical Academic Track program. Dr Reiner was
supported by grants R01HL146500 and R01HL132947
第一作者机构：[1]Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China[2]Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, China
共同第一作者：
通讯作者：
通讯机构：[1]Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China[2]Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, China[3]Centre for Global Health Research, Usher Institute, University of Edinburgh, UK[4]MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, UK[6]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden[47]State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China[*1]Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, 2nd Nanjiang Rd, Nansha District, 511458 Guangzhou, PR China[*2]Centre for Global Health Research, Usher Institute, University of Edinburgh, Old Medical School, Teviot Place, EH8 9AG Edinburgh, UK
推荐引用方式(GB/T 7714)：
Zhijian Yang,Erin Macdonald-Dunlop,Jiantao Chen,et al.Genetic Landscape of the ACE2 Coronavirus Receptor.[J].CIRCULATION.2022,145(18):1398-1411.doi:10.1161/CIRCULATIONAHA.121.057888.
APA：
Zhijian Yang,Erin Macdonald-Dunlop,Jiantao Chen,Ranran Zhai,Ting Li...&Xia Shen.(2022).Genetic Landscape of the ACE2 Coronavirus Receptor..CIRCULATION,145,(18)
MLA：
Zhijian Yang,et al."Genetic Landscape of the ACE2 Coronavirus Receptor.".CIRCULATION 145..18(2022):1398-1411
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