{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:11:15Z","timestamp":1793412675414,"version":"4.5.0"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"7917","license":[{"start":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T00:00:00Z","timestamp":1646611200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T00:00:00Z","timestamp":1646611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2022,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care\n                    <jats:sup>1<\/jats:sup>\n                    or hospitalization\n                    <jats:sup>2\u20134<\/jats:sup>\n                    after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (\n                    <jats:italic>IL10RB<\/jats:italic>\n                    and\n                    <jats:italic>PLSCR1<\/jats:italic>\n                    ), leucocyte differentiation (\n                    <jats:italic>BCL11A<\/jats:italic>\n                    ) and blood-type antigen secretor status (\n                    <jats:italic>FUT2<\/jats:italic>\n                    ). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes\u2014including reduced expression of a membrane flippase (\n                    <jats:italic>ATP11A<\/jats:italic>\n                    ), and increased expression of a mucin (\n                    <jats:italic>MUC1<\/jats:italic>\n                    )\u2014in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (\n                    <jats:italic>SELE<\/jats:italic>\n                    ,\n                    <jats:italic>ICAM5<\/jats:italic>\n                    and\n                    <jats:italic>CD209<\/jats:italic>\n                    ) and the coagulation factor\n                    <jats:italic>F8<\/jats:italic>\n                    , all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.\n                  <\/jats:p>","DOI":"10.1038\/s41586-022-04576-6","type":"journal-article","created":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T12:03:48Z","timestamp":1646654628000},"page":"97-103","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":313,"title":["Whole-genome sequencing reveals host factors underlying critical 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