{"doi":"10.17863/cam.84347","title":"Genetic landscape of the ACE2 coronavirus receptor","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 cardio- vascular 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 novels, 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.","journal":"Newcastle University ePrints (Newcastle Univesity)","year":2022,"id":296469,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":37,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9589,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":108537,"name":"Erin Macdonald-Dunlop","orcid":"0000-0001-6569-6086","position":1,"is_corresponding":false},{"id":81304,"name":"Jiantao Chen","orcid":"0000-0002-7214-2257","position":2,"is_corresponding":false},{"id":55712,"name":"Bram P. Prins","orcid":"0000-0001-5774-034X","position":3,"is_corresponding":false},{"id":51457,"name":"Eleanor Wheeler","orcid":"0000-0002-8616-6444","position":4,"is_corresponding":false},{"id":2348,"name":"Maik Pietzner","orcid":"0000-0003-3437-9963","position":5,"is_corresponding":false},{"id":108520,"name":"James E. Peters","orcid":"0000-0002-9415-3440","position":6,"is_corresponding":false},{"id":21909,"name":"Claudia Langenberg","orcid":"0000-0002-5017-7344","position":7,"is_corresponding":false},{"id":49710,"name":"Adam S. Butterworth","orcid":"0000-0002-6915-9015","position":8,"is_corresponding":false},{"id":25010,"name":"Alex P. Reiner","orcid":"0000-0002-1427-4470","position":9,"is_corresponding":false},{"id":21989,"name":"James F. Wilson","orcid":"0000-0001-5751-9178","position":10,"is_corresponding":false},{"id":561736,"name":"Xia Shen","orcid":"0000-0003-4390-1979","position":11,"is_corresponding":false},{"id":882204,"name":"Zhijian Yang","orcid":"0000-0003-4803-8633","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T00:31:16.555318Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}