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An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility
- Source :
- medRxiv, article-version (status) pre, article-version (number) 1, Genome Medicine, Genome Medicine, Vol 13, Iss 1, Pp 1-19 (2021)
- Publication Year :
- 2020
- Publisher :
- Cold Spring Harbor Laboratory, 2020.
-
Abstract
- Background While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility. Results Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb)) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs associated with both severe COVID-19 and other human traits demonstrated colocalization of the GWAS signal at the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN). This finding points to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity. Conclusions Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches. The iCPAGdb web portal is accessible at http://cpag.oit.duke.edu and the software code at https://github.com/tbalmat/iCPAGdb.
- Subjects :
- Multifactorial Inheritance
Linkage disequilibrium
Systems biology
Single-nucleotide polymorphism
Genome-wide association study
Locus (genetics)
Computational biology
QH426-470
Biology
Polymorphism, Single Nucleotide
Article
colocalization
Linkage Disequilibrium
Transcriptome
gout
rs2869462
pleiotropy
Genetic variation
Genetics
rs505922
Humans
Genetic Predisposition to Disease
Molecular Biology
Genetics (clinical)
Mechanism (biology)
SARS-CoV-2
macular telangiectasia
PheWAS
COVID-19
rs12610495
idiopathic pulmonary fibrosis
Phenotype
Human genetics
Genetic architecture
Hi-HOST
Medicine
Molecular Medicine
LD-score
Databases, Nucleic Acid
Software
cross-phenotype association
Genome-Wide Association Study
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- medRxiv, article-version (status) pre, article-version (number) 1, Genome Medicine, Genome Medicine, Vol 13, Iss 1, Pp 1-19 (2021)
- Accession number :
- edsair.doi.dedup.....746fc7b1a6c15759a266e26aadcaf580