Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome-sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19; (ii) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly available through the Regeneron Genetics Center COVID-19 Results Browser.

Severe COVID-19 Patients Show an Increase in Soluble TNFR1 and ADAM17, with a Relationship to Mortality

“…Recently, Saleh et al [32] reported that the A allele of the TNF G-308 A promoter variant (rs1800629) is associated with a more aggressive COVID-19 pattern, and authors suggested that the use of anti-TNF therapy may be promising in those patients. Although this variant has also been related to differences in protein expression in other lung diseases [33,34], unfortunately the G-308/severe COVID-19 association failed to be validated in larger studies in other populations [35,36]. We found no evidence of an association between TNF, TNFRSF1A, and TNFRSF1B gene variants with regard to COVID-19 severity, but we did see a trend of TNFRSF1A polymorphism, suggesting that with greater power we could have produced more significant findings.…”

Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia. Reply.

“…Most importantly, our negative findings are in full agreement with the recently published independent study of 586,157 individuals, including 20,952 cases of COVID-19 (4,928 hospitalized and 1,304 requiring ventilation or resulting in death) (5). There were no significant associations with any of the 13 candidate genes examined either individually or in aggregate, or when comparisons included all hospitalized cases or only the most severe cases.…”

Exome sequencing and analysis of 454,787 UK Biobank participants

“…We aggregated rare variants for gene burden testing as previously described 39 . In brief, rare variants were collapsed by gene region, such that individuals who are homozygous reference for all variants are considered homozygous reference, heterozygous carriers of any aggregated variant are considered heterozygous, and only minor allele homozygotes for an aggregated variant are considered as minor allele homozygotes.…”