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ACE2 Netlas: In-silico functional characterization and drug-gene interactions of ACE2 gene network to understand its potential involvement in COVID-19 susceptibility.
Pathak, Gita A; Wendt, Frank R; Goswami, Aranyak; Angelis, Flavio De; Polimanti, Renato.
  • Pathak GA; Yale School of Medicine, Department of Psychiatry, Division of Human Genetics, New Haven, CT Veteran Affairs Connecticut Healthcare System, West Haven, CT.
  • Wendt FR; Yale School of Medicine, Department of Psychiatry, Division of Human Genetics, New Haven, CT Veteran Affairs Connecticut Healthcare System, West Haven, CT.
  • Goswami A; Yale School of Medicine, Department of Psychiatry, Division of Human Genetics, New Haven, CT Veteran Affairs Connecticut Healthcare System, West Haven, CT.
  • Angelis F; Yale School of Medicine, Department of Psychiatry, Division of Human Genetics, New Haven, CT Veteran Affairs Connecticut Healthcare System, West Haven, CT.
  • Polimanti R; Yale School of Medicine, Department of Psychiatry, Division of Human Genetics, New Haven, CT Veteran Affairs Connecticut Healthcare System, West Haven, CT.
medRxiv ; 2020 Oct 28.
Article in English | MEDLINE | ID: covidwho-915979
ABSTRACT
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 a multi-level characterization of genes that interact with ACE2 (ACE2-gene network) for their over-represented 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 characterized functional consequences (among others) using miRNA binding-site targets. MiRNAs affected by ACE2-network variants revealed statistical over-representation of inflammation, aging, diabetes, and heart conditions. With respect to variants mapped to the ACE2-network, we observed COVID-19 related associations in RORA, SLC12A6 and SLC6A19 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/.

Full text: Available Collection: International databases Database: MEDLINE Topics: Variants Language: English Year: 2020 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Topics: Variants Language: English Year: 2020 Document Type: Article