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

Abstract

Abstract The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as a previous case-control genome-wide association study by the COVID-19 Host Genetics Initiative (HGI) identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3,904 COVID-19 patients from the GEN-COVID and other European series included in the EGAS00001005304 study of the COVID-19 HGI. Patients were genotyped using Illumina Infinium Global Screening Arrays. We carried out data quality check, principal component analysis, imputed the data, and performed survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. Results of the analyses showed a genome-wide significant (P-value < 5.0x10-8) association of the rs117011822 variant, on chromosome 11, and association, approaching the genome-wide threshold, of rs7208524 (P-value = 5.19x10-8), on chromosome 17. A total of 113 variants were associated with survival at P-value < 1.0x10-5 and most of them had gene expression regulatory functions as expression quantitative trait loci, mainly involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways.