Abstract
PURPOSE: It is critical to identify putative causal targets for SARS coronavirus 2, which may guide drug repurposing options to reduce the public health burden of COVID-19. METHODS: We applied complementary methods and multiphased design to pinpoint the most likely causal genes for COVID-19 severity. First, we applied cross-methylome omnibus (CMO) test and leveraged data from the COVID-19 Host Genetics Initiative (HGI) comparing 9,986 hospitalized COVID-19 patients and 1,877,672 population controls. Second, we evaluated associations using the complementary S-PrediXcan method and leveraging blood and lung tissue gene expression prediction models. Third, we assessed associations of the identified genes with another COVID-19 phenotype, comparing very severe respiratory confirmed COVID versus population controls. Finally, we applied a fine-mapping method, fine-mapping of gene sets (FOGS), to prioritize putative causal genes. RESULTS: Through analyses of the COVID-19 HGI using complementary CMO and S-PrediXcan methods along with fine-mapping, XCR1, CCR2, SACM1L, OAS3, NSF, WNT3, NAPSA, and IFNAR2 are identified as putative causal genes for COVID-19 severity. CONCLUSION: We identified eight genes at five genomic loci as putative causal genes for COVID-19 severity.