Angiotensin-converting enzyme-2 ( ACE2 ) receptor has been identified as the key adhesion molecule for the transmission of the SARS-CoV-2. However, there is no evidence that human genetic variation in ACE2 is singularly responsible for COVID-19 susceptibility. Therefore, we performed an integrative multi-level characterization of genes that interact with ACE2 (ACE2-gene network) for their statistically enriched biological properties in the context of COVID-19. The phenome-wide association of 51 genes including ACE2 with 4,756 traits categorized into 26 phenotype categories, showed enrichment of immunological, respiratory, environmental, skeletal, dermatological, and metabolic domains ( p < 4e-4). Transcriptomic regulation of ACE2-gene network was enriched for tissue-specificity in kidney, small intestine, and colon ( p < 4.7e-4). Leveraging the drug-gene interaction database we identified 47 drugs, including dexamethasone and spironolactone, among others. Considering genetic variants within ± 10 kb of ACE2-network genes we identified miRNAs whose binding sites may be altered as a consequence of genetic variation. The identified miRNAs revealed statistical over-representation of inflammation, aging, diabetes, and heart conditions. The genetic variant associations in RORA , SLC12A6 , and SLC6A19 genes were observed in genome-wide association study (GWAS) of COVID-19 susceptibility. We also report the GWAS-identified variant in 3p21.31 locus, serves as trans-QTL for RORA and RORC genes. Overall, functional characterization of ACE2-gene network highlights several potential mechanisms in COVID-19 susceptibility. The data can also be accessed at https://gpwhiz.github.io/ACE2Netlas/ .
【저자키워드】 COVID-19, ACE2, immune response, miRNA, network, 【초록키워드】 Dexamethasone, Inflammation, variant, drugs, Transmission, diabetes, database, binding site, kidney, Genetic variation, Genome-wide association study, phenotype, Genetic variant, GWAS, receptor, COVID-19 susceptibility, association, Evidence, Interaction, skeletal, Colon, Regulation, SLC6A19, locus, potential mechanism, small intestine, domain, categories, human genetic variation, Genes, immunological, statistical, highlight, responsible, performed, functional, conditions, statistically, biological property, RORA, RORC, SLC12A6, the SARS-CoV-2, 【제목키워드】 characterization, Involvement, Potential,