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 infected with SARS-COV-2. Several genome-wide association studies have identified human genomic risk single nucleotide polymorphisms (SNPs) associated with coronavirus disease 2019 (COVID-19) severity. However, the causal tissues or cell types underlying COVID-19 severity are uncertain. In addition, candidate genes associated with these risk SNPs were investigated based on 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 risk SNPs with transcription 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 and epithelium cells. These two aggregated regulatory networks were investigated to reveal their association with risk SNPs’ regulation. Two genomic clusters, the chemokine receptors cluster and the oligoadenylate synthetase (OAS) cluster, showed the strongest association with COVID-19 severity, and they had different regulatory programs in immune and epithelium contexts. Our findings were supported by analysis of both SNP array and whole genome sequencing-based genome wide association study (GWAS) summary statistics. Supplementary Information The online version contains supplementary material available at 10.1007/s43657-022-00066-x.

CovEpiAb: a comprehensive database and analysis resource for immune epitopes and antibodies of human coronaviruses

“…For viruses, it is essential to analyze the evolution of coronavirus and assess the immune escape caused by their mutations [ 82 , 83 ]. Similarly, a thorough understanding of the dynamic immune responses and diverse outcomes caused by coronaviruses is necessary for individual immunity [ 84 , 85 ]. Therefore, our future research will focus on analyzing antigenic epitope drift, immune cross-protection of emerging coronavirus variants and individual immune characteristics of virus-infected hosts.…”

Cohort profile: the China surgery and anesthesia cohort (CSAC)

“…Particularly, in December 2022, the Chinese government announced that COVID-19 restrictions would be eased, which led to a tremendous increase in COVID-19 cases in the cities where our included medical centres were located. We therefore additionally collected relevant data about COVID-19 infection from all recruited participants since January 2023, thus providing a unique opportunity for studying phenotypic and genotypic risk factors associated with COVID-19 symptoms and severity among the Chinese surgical population [11]. Our specific objectives include but are not limited to:…”

Heritability enrichment in context-specific regulatory networks improves phenotype-relevant tissue identification

“…For example, genetic variants in the regulatory network of cranial neural crest cells (CNCC) are elucidated on how they affect human facial morphology ( Feng et al, 2021 ). Regulatory networks can help identify two kinds of relevant cell types to COVID19 severity ( Feng et al, 2022b ). RSS-NET utilizes gene regulatory networks of multiple contexts and shows better tissue enrichment estimation by decomposing the total effect of an SNP through TF-TG regulations ( Zhu et al, 2021 ) and HiChIP RE-TG regulations ( Ma et al, 2022 ).…”