Conventional and Plasmacytoid Dendritic Cells Associated with Severe COVID-19: A Study of Integrating GWAS Summary Statistics and Single-Cell RNA-Seq Data

Background: Severe coronavirus disease 2019 (COVID-19) has been a critical threat to public health worldwide. Integrating the polygenic information from Genome-wide association study (GWAS) data with single-cell sequencing (scRNA-seq) data could provide further insights into factors associated with infection progression. However, previous integration analysis largely focused on predefined cell-type annotations but overlooked the heterogeneity of individual cells within cell types provided by scRNA-seq.Methods: GWAS summary statistics and scRNA-seq data on severe COVID-19 were downloaded from the COVID-19 Host Genetics Initiative and the Gene Expression Omnibus (GEO) database, respectively. MAGMA was used to perform a gene-based genetic association analysis and construct a weighted disease gene set. scDRS was to evaluate the association between individual cells with severe COVID-19 and prioritize relevant genes. A series of downstream analyses, including enrichment analysis, gene expression change patterns analysis, and cell-cell communication analysis, was used to explore and confirm the potential functional changes underlying these associations.Findings: scDRS identified a total of 6,657/130,211 cells (5.11%) significantly associated with severe infection. Genes related to antigen processing and presentation were positively associated with severe infection, while those related to T cells activity and regulation showed negative associations. Severe infection-associated cells are distributed across all cell types. Cell-type-level analysis showed that conventional dendritic cells (cDCs) to plasmacytoid DC (pDCs) were significantly associated with cell types. Genes enriched in IFN-related signaling pathways showed a fluctuated expression in both cDCs and pDCs, while those related to antigen processing and presentation were down-regulated in asymptomatic infection but gradually decreased with aggravation of infection. In addition, the absent of interaction signaling of MHC-II pathway from DCs to CD4+ naïve T cell and regulatory T cells (Treg) was observed in asymptomatic infection.Interpretation: All immune subtypes may have gotten involved in severe COVID-19, and antigen processing and presentation and regulation of T cells activity could be the severe infection-related pathway. Interferon-related functions in cDCs and pDCs and antigen presentation signals from cDCs and pDCs changed across infection states and may play important roles in infection progression, which needed further experiments to prove and dissect the underlying molecular mechanisms.Funding: This study was made possible by the generous support of the Natural Science Foundation of China [grant number 82173585, 82273741], Natural Science Foundation of Jiangsu Higher Education Institutions of China [grant number 21KJB330005, 22KJB330007], Priority Academic Program Development of Jiangsu Higher Education Institutions, and the Nanjing Major Science and Technology Project [grant number 2021-11005].Declaration of Interest: The authors declare no competing interests.