Genetic regulation of OAS1 nonsense-mediated decay underlies association with risk of severe COVID-19 (preprint)

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 OAS1 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-{lambda}1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of OAS1. We suggest that genetically-regulated loss of OAS1 expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the OAS1 risk haplotypes.

Global patterns of genetic variation and association with clinical phenotypes at genes involved in SARS-CoV-2 infection (preprint)

The COVID-19 pandemic caused by SARS-COV-2 has had a devastating impact on population health. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (ACE2, TMPRSS2, DPP4, and LY6E). We analyzed novel data from 2,012 ethnically diverse Africans, 15,997 individuals of European (7,061) and African (8,916) ancestry recruited by the Penn Medicine BioBank (PMBB), and comparative data from 2,504 individuals from the 1000 Genomes project. At ACE2 we identified 41 non-synonymous variants, found to be at low frequency in most populations. However, three non-synonymous variants were frequent among Central African hunter-gatherers (CAHG) from Cameroon, and signatures of positive selection could be detected on haplotypes encompassing those variants. We also detected signatures of positive selection for variants at regulatory regions upstream of ACE2 in diverse African populations. At TMPRSS2, we identified 48 non-synonymous variants, several of which are common in global populations, and 13 amino acid changes that are fixed in the human lineage after divergence from Chimpanzee. At DPP4 and LY6E most variants were rare in global populations indicating that purifying selection is acting at these loci. At all four loci, we identified common non-coding variants associated with gene expression that vary in frequency across global populations. By analyzing electronic health records from the PMBB we discovered genetic associations with clinical phenotypes, such as respiratory failure with ACE2 and upper respiratory tract infection with DPP4. Our study provides new insights into global variation at genes potentially affecting susceptibility to SARS-CoV-2 infection.

Targeting the Coronavirus Nucleocapsid Protein through GSK-3 Inhibition (preprint)

The coronaviruses responsible for severe acute respiratory syndrome (SARS-CoV), COVID-19 (SARS-CoV-2), Middle East respiratory syndrome (MERS-CoV), and other coronavirus infections express a nucleocapsid protein (N) that is essential for viral replication, transcription, and virion assembly. Phosphorylation of N from SARS-CoV by glycogen synthase kinase 3 (GSK-3) is required for its function and inhibition of GSK-3 with lithium impairs N phosphorylation, viral transcription, and replication. Here we report that the SARS-CoV-2 N protein contains GSK-3 consensus sequences and that this motif is conserved in diverse coronaviruses, despite limited overall sequence conservation, raising the possibility that SARS-CoV-2 may be sensitive to GSK-3 inhibitors including lithium. We conducted a retrospective analysis of lithium use in patients from three major health systems who were PCR tested for SARS-CoV-2. We found that patients taking lithium have a significantly reduced risk of COVID-19 (odds ratio = 0.51 [0.34 - 0.76], p = 0.001). We also show that the SARS-CoV-2 N protein is phosphorylated by GSK-3. Knockout of GSK3A and GSK3B demonstrates that GSK-3 is essential for N phosphorylation. Alternative GSK-3 inhibitors block N phosphorylation and impair replication in SARS-CoV-2 infected lung epithelial cells in a cell-type dependent manner. Targeting GSK-3 may therefore provide a new approach to treat COVID-19 and future coronavirus outbreaks.

Common genetic variants identify therapeutic targets for COVID-19 and individuals at high risk of severe disease (preprint)

The need to identify and effectively treat COVID-19 cases at highest risk for severe disease is critical. We identified seven common genetic variants (three novel) that modulate COVID-19 susceptibility and severity, implicating IFNAR2, CCHCR1, TCF19, SLC6A20 and the hyaluronan pathway as potential therapeutic targets. A high genetic burden was strongly associated with increased risk of hospitalization and severe disease among COVID-19 cases, especially among individuals with few known risk factors.