ABSTRACT
Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
Subject(s)
COVID-19 , Neoplasms, Glandular and EpithelialABSTRACT
COVID-19 is one of the most consequential pandemics in the last century, yet the biological mechanisms that confer disease risk are incompletely understood. Further, heterogeneity in disease outcomes is influenced by race, though the relative contributions of structural/social and genetic factors remain unclear. Very recent unpublished work has identified two genetic risk loci that confer greater risk for respiratory failure in COVID-19: the ABO locus and the 3p21.31 locus. To understand how these loci might confer risk and whether this differs by race, we utilized proteomic profiling and genetic information from three cohorts including black and white participants to identify proteins influenced by these loci. We observed that variants in the ABO locus are associated with levels of CD209/DC-SIGN, a known binding protein for SARS-CoV and other viruses, as well as multiple inflammatory and thrombotic proteins, while the 3p21.31 locus is associated with levels of CXCL16, a known inflammatory chemokine. Thus, integration of genetic information and proteomic profiling in biracial cohorts highlights putative mechanisms for genetic risk in COVID-19 disease.