Identification of Novel Genomic Variants in COVID-19 Patients Using Whole-Exome Sequencing: Exploring the Plausible Targets of Functional Genomics

Abstract

Covid-19 caused by SARS-CoV-2 virus has emerged as an immense burden and an unparalleled global health challenge in recorded human history. The clinical characteristics and risk factors of COVID-19 exhibit considerable variability, leading to a spectrum of clinical severity. Moreover, the likelihood of exposure to the virus may differ based on comorbidity status as comorbid illnesses have mechanisms that can considerably increase mortality by reducing the body's ability to withstand injury. The mammalian target of rapamycin (mTOR) pathway is essential for orchestrating innate immune cell defense, including cytokine production and is dysregulated in severe Coronavirus Disease 2019 (COVID-19) individuals. Through genome-wide, association studies, numerous genetic variants in the human host have been identified that have a significant impact on the immune response to SARS-CoV-2. To identify potentially significant genetic variants in Covid-19 patients that could affect the risk, severity, and clinical outcome of the infection, this study has used whole-exome sequencing (WES) on the 16 COVID-19 patients with varying comorbidities and severity of the disease including fatal outcomes. Among them, 8 patients made a full recovery and were discharged, while 8 patients unfortunately did not survive due to the severity of the illness and majority of them were males. The study identified 10,204 variants in the patients. From 1120 variants, which were chosen for novel variant analysis using mutation, function prediction tools to identify deleterious variants that could affect normal gene function, 116 variants of 57 genes were found to be deleterious. These variants were further classified as likely pathogenic and variants of uncertain significance. The data showed that among the likely pathogenic variants five genes were identified in connection to immune response whereas two were related to respiratory system. The common variants associated with the covid-19 phenotype showed the top 10 significant genes identified in this study such as ERCC2, FBXO5, HTR3D, FAIM, DNAH17, MTOR, IGHMBP2, ZNF530, QSER1, and FOXRED2 with variant rs1057079 of the MTOR gene representing the highest odds ratio (1.7, p = 8.7e-04). The mammalian target of rapamycin (mTOR) pathway variant rs1057079 was reported with high odds ratio, may orchestrate innate immune cell defense, including cytokine production, and is dysregulated. This study concluded that the mTOR signaling gene variant (rs1057079) is associated with different degrees of covid-19 severity and is essential for orchestrating innate immune cell defense including cytokine production. Inhibiting mTOR and its corresponding deleterious immune responses with medicinal approaches may provide a novel avenue for treating severe COVID-19 illness. Besides the PPI network exhibited a significantly high local clustering coefficient of 0.424 (p = 0.000536), suggesting the presence of tightly knit functional modules. These findings enhance our comprehension of the intricate interactions between genetic factors and COVID-19 disease.

Keywords: Covid-19; Functional genomics; Pathogenic variants; The mechanistic target of rapamycin (mTOR); Whole-exome sequencing.