A genome-wide association study for survival from a multi-center European study identified variants associated with the risk of death due to COVID-19

Background/Objectives: It has been demonstrated the inter-individual susceptibility to SARS-CoV-2 infection and variability in COVID-19 severity are in part due to host genetics. Among the GWASs so far performed, none looked for variants associated with mortality by analyzing the association between genotypes and time-to-event data. Methods: We performed a case-only genome-wide survival analysis, 60 days after infection/hospitalization, of 3,904 COVID-19 patients from the GEN-COVID cohort and other European cohorts included in the EGAS00001005304 study. Patients were genotyped using Illumina Infinium Global Screening Arrays. PLINK software was used for data quality check and principal component analysis. Imputation was carried out using the TopMed server. GeneAbel R package was used for survival analysis and age, sex, cohort, time of infection, and the first ten principal components were used as covariates in the Cox model. Results: Four variants associated with survival at P-value<5.0x10-8 and 13 at false discovery rate (FDR) < 0.10. Their minor alleles were associated with a higher mortality risk. Five variants are intergenic, the top one is upstream FGF19 gene, one is intronic of GPRC5C gene, and six are intronic of PSD3 gene. Looking at the 281 variants with a P-value<1.0x10-5, we found that 19 variants mapped in this latter locus, another 20 mapped in a locus on chromosome 6, and 77 polymorphisms map on chromosome 9, in WDR5 locus. Conclusion: These results suggest that COVID-19 mortality risk variants differed from those associated with susceptibility and severity. Grant References: "PATCOVID" - 2020-2016_Ric_3 - Istituto Buddista Italiano Soka Gakkai