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

Covid-19 is a contagious disease caused by SARS-CoV-2, a novel severe acute respiratory syndrome coronavirus. Common variants and networks underlying host genetic mechanisms have been extensively studied to identify disease-associated genetic factors. However, there are few studies about the rare variants, typically inborn errors of immunity, in understanding the host genetics behind Covid-19 infection, especially in the Chinese population. To fill this gap, we investigate likely-deleterious missense and high-confidence predicted loss-of-function variants by (a) performing gene- and pathway-level association analyses, (b) examining known genes involved in type I interferon signaling and others previously reported in Covid-19 disease, and (c) identifying candidate genes with accumulating mutations and their potential protein-protein interactions with known genes. Based on our analyses, several putative genes and pathways are uncovered and worth further investigation, for example, genes IL12RB1, TBK1, and TLR3, and pathways Tuberculosis (hsa:05152), Primary Immunodeficiency (hsa:05340), and Influenza A (hsa:05164). 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 to some extent, as an acute inflammatory disease, Covid-19 is also affected by these inborn errors of immunity. We hope that the identification of these rare genetic factors will provide new insights into the genetic architecture of Covid-19.

Plasma cell-free DNA promise disease monitoring and tissue injury assessment of COVID-19 (preprint)

COVID-19 is a huge threat to global health. Due to the lack of definitive etiological therapeutics currently, effective disease monitoring is of high clinical value for better healthcare and management of the large number of COVID-19 patients. In this study, we recruited 37 COVID-19 patients, collected 176 blood samples upon diagnosis and during treatment, and analyzed cell-free DNA (cfDNA) in these samples. We report gross abnormalities in cfDNA of COVID-19 patients, including elevated GC content, altered molecule size and end motif patterns. More importantly, such cfDNA characteristics reflect patient-specific physiological conditions during treatment. Further analysis on tissue origin tracing of cfDNA reveals frequent tissue injuries in COVID-19 patients, which is supported by clinical diagnoses. Hence, we demonstrate the translational merit of cfDNA as valuable analyte for effective disease monitoring, as well as tissue injury assessment in COVID-19 patients.

A Chinese host genetic study discovered type I interferons and causality of cholesterol levels and WBC counts on COVID-19 severity (preprint)

As of early May 2021, the ongoing pandemic COVID-19 has caused over 160 million of infections and over 3 million deaths worldwide. Many risk factors, such as age, gender, and comorbidities, have been studied to explain the variable symptoms of infected patients. However, these effects may not fully account for the diversity in disease severity. Here, we present a comprehensive analysis of a broad range of patients laboratory and clinical assessments to investigate the genetic contributions to COVID-19 severity. By performing GWAS analysis, we discovered several concrete associations for laboratory features. Based on these findings, we performed Mendelian randomization (MR) analysis to investigate the causality of laboratory traits on disease severity. From the MR study, we identified two causal traits, cholesterol levels and WBC counts. The functional gene related to cholesterol levels is ApoE and people with particular ApoE genotype are more likely to have higher cholesterol levels, facilitating the process that SARS-CoV-2 binds on its receptor ACE2 and aggravating COVID-19 disease. The functional gene related to WBC counts is MHC system that plays a central role in the immune system. The host immune response to the SARS-CoV-2 infection greatly affects the patients severity status and clinical outcome. Additionally, our gene-based and GSEA analysis revealed interferon pathways, including type I interferon receptor binding, regulation of IFNA signaling, and SARS coronavirus and innate immunity. We hope that our work will make a contribution in studying the genetic mechanisms of disease illness and serve as useful reference for the clinical diagnosis and treatment of COVID-19.

Time-series plasma cell-free DNA analysis reveals disease severity of COVID-19 patients (preprint)

Symptoms of coronavirus disease 2019 (COVID-19) range from asymptomatic to severe pneumonia and death. Detection of individuals at high risk for critical condition is crucial for control of the disease. Herein, for the first time, we profiled and analyzed plasma cell-free DNA (cfDNA) of mild and severe COVID-19 patients. We found that in comparison between mild and severe COVID-19 patients, Interleukin-37 signaling was one of the most relevant pathways; top significantly altered genes included POTEH, FAM27C, SPATA48, which were mostly expressed in prostate and testis; adrenal glands, small intestines and liver were tissues presenting most differentially expressed genes. Our data thus revealed potential tissue involvement, provided insights into mechanism on COVID-19 progression, and highlighted utility of cfDNA as a noninvasive biomarker for disease severity inspections.