TY - JOUR
T1 - ACE2 Netlas
T2 - In silico Functional Characterization and Drug-Gene Interactions of ACE2 Gene Network to Understand Its Potential Involvement in COVID-19 Susceptibility
AU - COVID-19 Host Genetics Initiative
AU - Pathak, Gita A
AU - Wendt, Frank R
AU - Goswami, Aranyak
AU - Koller, Dora
AU - De Angelis, Flavio
AU - Polimanti, Renato
AU - van de Beek, Diederik
N1 - Funding Information: We thank the COVID-19 Host Genetics Initiative (https://www.covid19hg.org/acknowledgements/) for providing open access to genetic association data. The content of this manuscript has been presented at the American Society of Human Genetics (Virtual) 2020 (https://www.abstractsonline.com/pp8/#!/9070/presentation/1977). Funding. We would like to acknowledge support from the National Institutes of Health (R21 DC018098, R21 DA047527 and F32 MH122058). Funding Information: We would like to acknowledge support from the National Institutes of Health (R21 DC018098, R21 DA047527 and F32 MH122058). Publisher Copyright: © Copyright © 2021 Pathak, Wendt, Goswami, Koller, De Angelis, COVID-19 Host Genetics Initiative and Polimanti. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/8/27
Y1 - 2021/8/27
N2 - 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/.
AB - 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/.
KW - ACE2
KW - COVID-19
KW - immune response
KW - miRNA
KW - network
UR - http://www.scopus.com/inward/record.url?scp=85114887539&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fgene.2021.698033
DO - https://doi.org/10.3389/fgene.2021.698033
M3 - Article
C2 - 34512723
SN - 1664-8021
VL - 12
SP - 698033
JO - Frontiers in genetics
JF - Frontiers in genetics
M1 - 698033
ER -