Exome-Wide Association Study Reveals Host Genetic Variants Likely Associated with the Severity of COVID-19 in Patients of European Ancestry

Abstract

Host genetic variability plays a pivotal role in modulating COVID-19 clinical outcomes. Despite the functional relevance of protein-coding regions, rare variants located here are less likely to completely explain the considerable numbers of acutely affected COVID-19 patients worldwide. Using an exome-wide association approach, with individuals of European descent, we sought to identify common coding variants linked with variation in COVID-19 severity. Herein, cohort 1 compared non-hospitalized (controls) and hospitalized (cases) individuals, and in cohort 2, hospitalized subjects requiring respiratory support (cases) were compared to those not requiring it (controls). 229 and 111 variants differed significantly between cases and controls in cohorts 1 and 2, respectively. This included FBXO34, CNTN2, and TMCC2 previously linked with COVID-19 severity using association studies. Overall, we report SNPs in 26 known and 12 novel candidate genes with strong molecular evidence implicating them in the pathophysiology of life-threatening COVID-19 and post-recovery sequelae. Of these few notable known genes include, HLA-DQB1, AHSG, ALOX5AP, MUC5AC, SMPD1, SPG7, SPEG,GAS6, and SERPINA12. These results enhance our understanding of the pathomechanisms underlying the COVID-19 clinical spectrum and may be exploited to prioritize biomarkers for predicting disease severity, as well as to improve treatment strategies in individuals of European ancestry.

COVID-19 Prevention and Treatment

“…Five of the papers of the Special Issue focus on the general and specific conditions of COVID-19 pathology [ 29 , 30 , 31 , 32 , 33 ]: one paper explored the potential role of inflammation as a prognostic hallmark of clinical outcome in infected patients. The main objective of a second study was to describe the role of host genetic variability in modulating COVID-19 clinical outcomes.…”

Human genetic determinants of COVID-19 in Brazil: challenges and future plans

“…The group also investigated the phenotypes previously described as associated with the tag-SNP for this locus (rs11240388), and these were mainly related to hematological traits, including immune cell count and morphology. Interestingly, Upadhyai et al (2022 ) found an association of common coding variants in two genes of this region ( CNTN2 and TMCC2 ) also evaluating individuals of European ancestry. Finally, one WES-based Brazilian study focused on identifying associations related to HLA alleles with COVID-19.…”

COVID-19 progression towards ARDS: a genome wide study reveals host factors underlying critical COVID-19

“…In this study, 26 single nucleotide polymorphisms (SNPs) in genes and 12 unique candidates with biological function or strong supporting evidence were discovered. pointing to a high likelihood of participation in altering the clinical phenotype of COVID-19 [17].…”