Human genetic variants associated with COVID-19 severity are enriched in immune and epithelium regulatory networks

Abstract

Human genetic variants can influence the severity of symptoms being infected with SARS-COV-2. Several genome-wide association studies have identified human genomic risk SNPs associated with COVID-19 severity. However, the causal tissues or cell types of COVID-19 severity are uncertain and candidate genes associated with these human risk SNPs were investigated in genomic proximity instead of their functional cellular contexts. Here, we compiled regulatory networks of 77 human contexts and revealed those risk SNPs enriched cellular contexts and associated transcript factors, regulatory elements, and target genes. Twenty-one human contexts were identified and grouped into two categories: immune cells and epithelium cells. We further aggregated the regulatory networks of immune cells, epithelium cells, and immune-epithelium crosstalk and investigated their association with risk SNPs regulation. Two genomic clusters, chemokine receptors cluster and OAS cluster, showed the strongest association with COVID-19 severity and different regulations in immune and epithelium contexts. Our findings were supported by analysis on both microarray and whole genome sequencing based GWAS summary statistics.