Rare Variants in Inborn Errors of Immunity Genes Associated with Covid-19 Severity

Host genetic factors have been shown to play an important role in SARS-CoV-2 infection and the course of Covid-19 disease. The genetic contributions of common variants influencing Covid-19 susceptibility and severity have been extensively studied in diverse populations. However, the studies of rare genetic defects arising from inborn errors of immunity (IEI) are relatively few, especially in the Chinese population. To fill this gap, we used a deeply sequenced dataset of nearly 500 patients, all of Chinese descent, to investigate putative functional rare variants. Specifically, we annotated rare variants in our call set and selected likely deleterious missense (LDM) and high-confidence predicted loss-of-function (HC-pLoF) variants. Further, we analyzed LDM and HC-pLoF variants between non-severe and severe Covid-19 patients by (a) performing gene- and pathway-level association analyses, (b) testing the number of mutations in previously reported genes mapped from LDM and HC-pLoF variants, and (c) uncovering candidate genes via protein-protein interaction (PPI) network analysis of Covid-19-related genes and genes defined from LDM and HC-pLoF variants. From our analyses, we found that (a) pathways Tuberculosis (hsa:05152), Primary Immunodeficiency (hsa:05340), and Influenza A (hsa:05164) showed significant enrichment in severe patients compared to the non-severe ones, (b) HC-pLoF mutations were enriched in Covid-19-related genes in severe patients, and (c) several candidate genes, such as IL12RB1, TBK1, TLR3, and IFNGR2, are uncovered by PPI network analysis and worth further investigation. These regions generally play an essential role in regulating antiviral innate immunity responses to foreign pathogens and in responding to many inflammatory diseases. We believe that our identified candidate genes/pathways can be potentially used as Covid-19 diagnostic markers and help distinguish patients at higher risk.