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

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/.

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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

10.1101/2020.10.27.20220665 ◽

2020 ◽

Author(s):

Gita A Pathak ◽

Frank R Wendt ◽

Aranyak Goswami ◽

Flavio De Angelis ◽

Renato Polimanti ◽

...

Keyword(s):

Gene Network ◽

Functional Characterization ◽

Gene Interaction ◽

Biological Properties ◽

Angiotensin Converting Enzyme 2 ◽

Interaction Database ◽

Functional Consequences ◽

Multi Level ◽

Ace2 Gene

AbstractAngiotensin-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/

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O4-04-04: TOWARD FINE MAPPING AND FUNCTIONAL CHARACTERIZATION OF GENOME-WIDE ASSOCIATION STUDY-IDENTIFIED LOCUS RS74615166 (TRIP4) FOR ALZHEIMER'S DISEASE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2014.04.405 ◽

2014 ◽

Vol 10 ◽

pp. P257-P258 ◽

Cited By ~ 1

Author(s):

Agustín Ruiz ◽

Stefanie Heilmann ◽

Markus Leber ◽

Tim Becker ◽

Mohammad Toliat ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Study ◽

Fine Mapping ◽

Genome Wide Association Study ◽

Functional Characterization ◽

Genome Wide Association ◽

Genome Wide

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Genome-wide identification of GMP genes in Rosaceae and functional characterization of FaGMP4 in strawberry (Fragaria × ananassa)

Genes & Genomics ◽

10.1007/s13258-021-01062-7 ◽

2021 ◽

Author(s):

Yuanxiu Lin ◽

Jiahao Zhang ◽

Lintai Wu ◽

Yunting Zhang ◽

Qing Chen ◽

...

Keyword(s):

Functional Characterization ◽

Fragaria Ananassa ◽

Genome Wide

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Genetic variation rs10484761 on 6p21.1 derived from a genome-wide association study is associated with gastric cancer survival in a Chinese population

Gene ◽

10.1016/j.gene.2013.11.087 ◽

2014 ◽

Vol 536 (1) ◽

pp. 59-64 ◽

Cited By ~ 10

Author(s):

Meiyun Kang ◽

Xiaojie Ding ◽

Ming Xu ◽

Haixia Zhu ◽

Sang Liu ◽

...

Keyword(s):

Gastric Cancer ◽

Genetic Variation ◽

Association Study ◽

Chinese Population ◽

Genome Wide Association Study ◽

Cancer Survival ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

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Functional Characterization of Genetic Variation in the Frizzled 1 (FZD1) Promoter and Association With Bone Phenotypes: More to the LRP5 Story?

Journal of Bone and Mineral Research ◽

10.1359/jbmr.080816 ◽

2009 ◽

Vol 24 (1) ◽

pp. 87-96 ◽

Cited By ~ 16

Author(s):

Laura M Yerges ◽

Yingze Zhang ◽

Jane A Cauley ◽

Candace M Kammerer ◽

Cara S Nestlerode ◽

...

Keyword(s):

Genetic Variation ◽

Functional Characterization

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Genetic variation associated with chromosomal aberration frequency: A genome-wide association study

Environmental and Molecular Mutagenesis ◽

10.1002/em.22236 ◽

2018 ◽

Vol 60 (1) ◽

pp. 17-28 ◽

Cited By ~ 5

Author(s):

Yasmeen Niazi ◽

Hauke Thomsen ◽

Bozena Smolkova ◽

Ludmila Vodickova ◽

Sona Vodenkova ◽

...

Keyword(s):

Genetic Variation ◽

Association Study ◽

Chromosomal Aberration ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Aberration Frequency ◽

Genome Wide ◽

A Genome

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Genome-wide identification and functional characterization of Camelina sativa WRKY gene family in response to abiotic stress

10.21203/rs.3.rs-36113/v3 ◽

2020 ◽

Author(s):

Yanan Song ◽

Hongli Cui ◽

Ying Shi ◽

Jinai Xue ◽

Chunli Ji ◽

...

Keyword(s):

Gene Family ◽

Stress Responses ◽

Stress Resistance ◽

Segmental Duplication ◽

Functional Characterization ◽

High Stress ◽

Camelina Sativa ◽

Genome Wide ◽

Large Expansion

Abstract Background: WRKY transcription factors are a superfamily of regulators involved in diverse biological processes and stress responses in plants. However, knowledge is limited for WRKY family in camelina (Camelina sativa), an important Brassicaceae oil crop with strong tolerance against various stresses. Here, genome-wide characterization of WRKY proteins is performed to examine their gene-structures, phylogenetics, expressions, conserved motif organizations, and functional annotation to identify candidate WRKYs mediating regulation of stress resistance in camelina.Results: Total of 242 CsWRKY proteins encoded by 224 gene loci distributed uneven on chromosomes were identified, and classified into three groups via phylogenetic analysis according to their WRKY domains and zinc finger motifs. 15 CsWRKY gene loci generated 33 spliced variants. Orthologous WRKY gene pairs were identified, with 173 pairs in C. sativa and Arabidopsis genomes as well as 282 pairs for C. sativa and B. napus, respectively. 137 segmental duplication events were observed but no tandem duplication in camelina genome. Ten major conserved motifs were examined, with WRKYGQK as the most conserved and several variants existed in many CsWRKYs. Expression analysis revealed that half more CsWRKY genes were expressed constitutively, and a set of them had a tissue-specific expression. Notably, 11 CsWRKY genes exhibited significantly expression changes in plant seedlings under cold, salt, and drought stress, respectively, having preferentially inducible expression pattern in response to the stress.Conclusions: The present described a detail analysis of CsWRKY gen family and their expression profiled in twelve tissues and under several stress conditions. Segmental duplication is the major force for large expansion of this gene family, and a strong purifying pressure happened for CsWRKY proteins evolutionally. CsWRKY proteins play important roles for plant development, with differential functions in different tissues. Exceptionally, eleven CsWRKYs, particularly five alternative spliced isoforms were found to be the key players possibly in mediating plant response to various stresses. Overall, our results provide a foundation for understanding roles of CsWRKYs and the precise mechanism through which CsWRKYs regulate high stress resistance to stress as well as development of stress tolerance cultivars for Cruciferae crops.

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