Whole genome sequencing identifies multiple loci for critical 1 illness caused by COVID-19 2

61 Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune 62 system. We and others have shown that host genetic variation influences the development of illness 63 requiring critical care 1 or hospitalisation 2;3;4 following SARS-Co-V2 infection. The GenOMICC 64 (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes 65 with population controls in order to find underlying disease mechanisms. 66 Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases 67 compared with 48,400 population controls to discover and replicate 22 independent 15 new independent within signalling indicates the risk allele. For each variant, we report the risk allele frequency in Europeans (RAF), the odds ratio and 95% confidence interval, and the association P -value. Consequence indicates the worst consequence predicted by VEP99, and Gene indicates the VEP99-predicted gene, but not necessarily the causal mediator. Expression indicates genes where is evidence of gene expression affecting COVID-19 severity, found by TWAS and colocalisation analysis. et al. 39 The credible set for the 257 FUT2 locus includes rs492602 (chr19:48703160:A:G) which is linked to a stop codon gain mutation 258 (chr19:48703417:G:A), leading to the well-described non-secretor phenotype in homozygotes. 40;41 We show that the stop-gain, allele is protective against life-threatening COVID-19.