An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility

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.

Host genetic factors determining COVID-19 susceptibility and severity

“…To investigate the role of ABO in COVID-19, it was investigated whether SNPs identified in 4418 GWASs of other disease traits were in linkage disequilibrium (LD) with observed earlier associations [29] . In previous GWASs, ABO associations with plasma levels of eight proteins had been reported, including factor VIII and von Willebrandt factor, IL-6, TNF-alpha, CD209 (DC-SIGN), Tie-1, mannose-binding protein C and fibroblast growth factor 23 [29] . The ABO association with coagulation factors suggests an influence on COVID-19 via enhanced coagulation, as reported in COVID-19 patients with CS [30] .…”

“…In further analyses, the authors focused on CD209, member of the C -type lectin family and alternative entry receptor for SARS-CoV-2 [31] . By means of colocalization analyses, a likely causal variant for increased CD209 expression, rs505922, was identified [29] . This trans-eQTL (expression quantitative trait locus) of CD209 was replicated in two MR studies employing HGI data.…”

“…In a recent GWAS, DPP9 was associated with susceptibility to idiopathic lung fibrosis (IPF) [58] . When looking at association signals at this locus, rs12610495, which is in strong LD with rs2109069, an eQTL in lung tissue for DPP9 led to decreased DPP9 levels, consistent with an increased risk of severe COVID-19 [ 29 , 59 ]. The study also examined lung transcriptome data from COVID-19 patients and found that DPP9 levels were increased compared to controls or patients with bacterial pneumonia.’…”

Neurotropism of SARS-CoV-2 and neurological diseases of the central nervous system in COVID-19 patients

“…OAS1 was associated with infantile pulmonary alveolar proteinosis that resulted in dyspnoea (Cho et al 2018 ). DPP9 is a serine protease with a role in cell adhesion and is a suggested candidate for pulmonary fibrosis (Initiative 2021 ; Zhou and Wang 2016 ; Fingerlin et al 2013 ; Wang et al 2021 ). The ABO blood group locus has also shown a significant association with COVID-19 disease/severity (Wang et al 2021 ; Initiative 2021 ).…”

“…DPP9 is a serine protease with a role in cell adhesion and is a suggested candidate for pulmonary fibrosis (Initiative 2021 ; Zhou and Wang 2016 ; Fingerlin et al 2013 ; Wang et al 2021 ). The ABO blood group locus has also shown a significant association with COVID-19 disease/severity (Wang et al 2021 ; Initiative 2021 ). An intronic variant of lysine acetyltransferase 8 (KAT8) regulatory NSL (non-specific lethal) complex subunit 1 (KANSL1 ) was protective in COVID-19 cases because it reduced the requirement for hospitalization (Initiative 2021 ).…”