AUTHOR=Pathak Gita A. , Wendt Frank R. , Goswami Aranyak , Koller Dora , De Angelis Flavio ,  COVID-19 Host Genetics Initiative , Polimanti Renato 

TITLE=ACE2 Netlas: In silico Functional Characterization and Drug-Gene Interactions of ACE2 Gene Network to Understand Its Potential Involvement in COVID-19 Susceptibility

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.698033

DOI=10.3389/fgene.2021.698033

ISSN=1664-8021

ABSTRACT=<p>Angiotensin-converting enzyme-2 (<italic>ACE2</italic>) 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 (<italic>p</italic> &lt; 4e-4). Transcriptomic regulation of ACE2-gene network was enriched for tissue-specificity in kidney, small intestine, and colon (<italic>p</italic> &lt; 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 <italic>RORA</italic>, <italic>SLC12A6</italic>, and <italic>SLC6A19</italic> 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 <italic>RORA</italic> and <italic>RORC</italic> genes. Overall, functional characterization of ACE2-gene network highlights several potential mechanisms in COVID-19 susceptibility. The data can also be accessed at <ext-link ext-link-type="uri" xlink:href="https://gpwhiz.github.io/ACE2Netlas/" xmlns:xlink="http://www.w3.org/1999/xlink">https://gpwhiz.github.io/ACE2Netlas/</ext-link>.</p>