Whole-genome sequencing reveals host factors underlying critical COVID-19

Abstract

A th an as ios Kousathanas, Erola Pairo-Castineira, Konrad Rawlik, Alex S tu ck ey , C hr is to ph er A. Odhams,

GWAS and meta-analysis identifies multiple new genetic mechanisms underlying severe Covid-19

“…The design of the GenOMICC study has been previously described. 3;4 Briefly, patients with confirmed Covid-19 requiring continuous cardiorespiratory monitoring or organ support (a generalisable definition for admission to a critical care area) were recruited in 2020-21. Using participants recruited and genotyped in GenOMICC and ISARIC4C since the first reported GenOMICC GWAS, 3 we performed ancestry-specific GWAS largely following the methods we previously described 3;4 (see Material and Methods, and Supplementary Material).…”

“…Characteristics of contributing studies to the meta analyses are summarised in Table 1 and Supplementary Table 1 for the critically ill and hospitalised phenotypes, with further details on each study provided in the Supplementary Material. Since leave-one-out analyses from the HGIv6 release were not available, we used a mathematical subtraction approach, as in our previous work, 4 ,to remove the GenOMICC signals from HGIv6, yielding an independent data set. This was essential because previous GenOMICC data contribute 20 to 50% of each genetic association signal in the HGI analyses.…”

“…Critical illness in Covid-19 is a relatively narrow clinical phenotype characterised by hypoxaemic respiratory failure 9 in which lung injury is, at least in part, caused by host-mediated inflammation. 1;2 The international GenOMICC (Genetics of Mortality in Critical Care) consortium has shown that critical illness is a highly efficient phenotype for discovery of genetic variants associated with Covid-19, 3;4 contributing the largest signal to recent meta-analyses 10 despite only including a relatively small number of patients. This is consistent with our previous predictions for other respiratory viral illnesses.…”

“… Abstract Pulmonary inflammation drives critical illness in Covid-19, 1;2 creating a clinically homogeneous extreme phenotype, which we have previously shown to be highly efficient for discovery of genetic associations. 3;4 Despite the advanced stage of illness, we have found that immunomodulatory therapies have strong beneficial effects in this group. 1;5 Further genetic discoveries may identify additional therapeutic targets to modulate severe disease.…”

Human genetic variants associated with COVID-19 severity are enriched in immune and epithelium regulatory networks

“…Higher resolution GWAS summary statistics hold the promise to reveal richer and more accurate genetic variants. We noticed that Kousathanas et al used whole genome sequencing data (WGS) of a larger cohort to conduct GWAS analysis and found 1,322 SNPs (P≤ 5 × 10 &' ) with significant association with severity with COVID-19 35 . We then used this independent data to validate and refine our relevant contexts and regulatory networks.…”