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

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.

Genomic and Ancestral Variation Underlies the Severity of COVID-19 Clinical Manifestation in Individuals of European Descent.

The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by a wide spectrum of clinical phenotypes ranging from asymptomatic to symptomatic with mild or moderate presentation and severe disease. COVID-19 susceptibility, severity and recovery have demonstrated high variability worldwide. Variances in the host genetic architecture may underlie the inter-individual and population-scale differences in COVID-19 presentation. We performed a genome-wide association analysis employing the genotyping data from AncestryDNA for COVID-19 patients of European descent and used asymptomatic subjects as the control group. We identified 621 genetic variants that were significantly distinct between asymptomatic and acutely symptomatic COVID-19 patients (multiple-testing corrected p-value < 0.001). These variants were found to be associated with pathways governing host immunity, such as interferon, interleukin and cytokine signalling, and known COVID-19 comorbidities, such as obesity and cholesterol metabolism. Further, our ancestry analysis revealed that the asymptomatic COVID-19 patients possess discernibly higher proportions of the Ancestral North Eurasian (ANE) and Eastern Hunter-Gatherer (EHG) ancestry, which was introduced to Europe through Bell Beaker culture (Yamnaya related) and lower fractions of Western Hunter-Gatherer (WHG) ancestry, while severely symptomatic patients have higher fractions of WHG and lower ANE/EHG ancestral components, thereby delineating the likely ancestral differences between the two groups.