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

Abstract

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care or hospitalisation following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study is designed to compare genetic variants in critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identified 15 new independent associations with severe COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in severe disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.

ELF5 is a respiratory epithelial cell-specific risk gene for severe COVID-19

“…4C). We note that our proteogenomic screen prioritised SFTPD as a candidate gene for severe COVID-19 in line with other studies 30,32 , leaving the possibility of potential interactions between candidate mediators.…”

“…The lead cis-pQTL for ELF5, rs766826 (MAF=35.9%), is in strong linkage disequilibrium (LD; r 2 =0.81) with a recently identified variant rs61882275 associated with severe COVID-19 in an independent study using whole genome sequencing 32 . The causal gene remained unidentified, but the two closest candidate genes are ELF5 and CAT , whose encoded protein products are both captured by our proteomic data.…”

Poking COVID-19: Insights on Genomic Constraints among Immune-Related Genes between Qatari and Italian Populations

“…A recent study [39] compared levels of MUC5AC, MUC1 and MUC1-CT between critical ill COVID-19 patients and healthy controls, finding a significantly higher level of those proteins in the patients' mucus. It is also worth noting that another recent work from Kousathanas et al reported a significant genome-wide association between variants in the MUC1 gene and critical illness caused by [9,39].…”

“…Host genomic information, specifically genomic variations, may characterize susceptibility to disease and identify people with a higher risk of harm, leading to better targeting of care and vaccination [5][6][7]. In addition, characterizing these host factors may help identifying and development of adapted drugs and vaccines [8][9][10]. The scientific community came together with several efforts to investigate how the genomic variation in the host affects disease susceptibility and progress [11,12].…”

Poking COVID-19: insights on genomic constraints among immune-related genes between Qatari and Italian populations

“…This protein plays a protective role against inhaled pathogens, like influenza [40]. A recent study [41] compared levels of MUC5AC, MUC1 and MUC1-CT between critical ill COVID-19 patients and healthy controls, finding a significantly higher level of those proteins in the patients' mucus. It is also worth noting that another recent work from Kousathanas et al reported a significant genome-wide association between variants in the MUC1 gene and critical illness caused by [41,42].…”