Integrating single-cell sequencing data with GWAS summary statistics reveals CD16+monocytes and memory CD8+T cells involved in severe COVID-19

Abstract

Background Understanding the host genetic architecture and viral immunity contributes to the development of effective vaccines and therapeutics for controlling the COVID-19 pandemic. Alterations of immune responses in peripheral blood mononuclear cells play a crucial role in the detrimental progression of COVID-19. However, the effects of host genetic factors on immune responses for severe COVID-19 remain largely unknown. Methods We constructed a computational framework to characterize the host genetics that influence immune cell subpopulations for severe COVID-19 by integrating GWAS summary statistics (N = 969,689 samples) with four independent scRNA-seq datasets containing healthy controls and patients with mild, moderate, and severe symptom (N = 606,534 cells). We collected 10 predefined gene sets including inflammatory and cytokine genes to calculate cell state score for evaluating the immunological features of individual immune cells. Results We found that 34 risk genes were significantly associated with severe COVID-19, and the number of highly expressed genes increased with the severity of COVID-19. Three cell subtypes that are CD16+monocytes, megakaryocytes, and memory CD8+T cells were significantly enriched by COVID-19-related genetic association signals. Notably, three causal risk genes of CCR1, CXCR6, and ABO were highly expressed in these three cell types, respectively. CCR1+CD16+monocytes and ABO+ megakaryocytes with significantly up-regulated genes, including S100A12, S100A8, S100A9, and IFITM1, confer higher risk to the dysregulated immune response among severe patients. CXCR6+ memory CD8+ T cells exhibit a notable polyfunctionality including elevation of proliferation, migration, and chemotaxis. Moreover, we observed an increase in cell-cell interactions of both CCR1+ CD16+monocytes and CXCR6+ memory CD8+T cells in severe patients compared to normal controls among both PBMCs and lung tissues. The enhanced interactions of CXCR6+ memory CD8+T cells with epithelial cells facilitate the recruitment of this specific population of T cells to airways, promoting CD8+T cell-mediated immunity against COVID-19 infection. Conclusions We uncover a major genetics-modulated immunological shift between mild and severe infection, including an elevated expression of genetics-risk genes, increase in inflammatory cytokines, and of functional immune cell subsets aggravating disease severity, which provides novel insights into parsing the host genetic determinants that influence peripheral immune cells in severe COVID-19.

Immune responses in mildly versus critically ill COVID-19 patients

“…This occurs by release of cytotoxic granules (154) and secretion of cytokines (164). Several studies reported lower CD8 + T cell counts in patients, even with mild or moderate, but especially with severe or critical COVID-19 (160,(165)(166)(167)(168). A decreased frequency of CD8 + T cells in non-survivors was reported until death (169).…”

Causal association of epigenetic aging and COVID-19 severity and susceptibility: A bidirectional Mendelian randomization study

“…In our "leave-one-out" analysis, we found that rs35081325 had a much greater impact on the results than other SNPs. Rs35081325 is located in the chr3p21 LZTFL1 intron subregion, and studies have shown that (34)(35)(36) the chr3p21 region where rs35081325 is located is closely related to COVID severity. The secondary allele (allele "T") of this gene has a protective effect.…”

COVID-GWAB: A Web-Based Prediction of COVID-19 Host Genes via Network Boosting of Genome-Wide Association Data

“…The p values from the GWAS data were used for the calculation of the odds of the association. We excluded genes encoding the major histocompatibility complex (MHC) molecules from the final candidates because their inflated associations with COVID-19 driven by the unusual genomic structures of MHC regions have been reported [ 14 , 15 , 16 ].…”