 Whole-genome sequencing reveals host factors underlying critical COVID-19Athanasios Kousathanas,
Erola Pairo-Castineira,
Konrad Rawlik,
Alex Stuckey,
Christopher A. Odhams,
Susan Walker,
Clark D. Russell,
Tomas Malinauskas,
Yang Wu,
Jonathan Millar,
Xia Shen,
Katherine S. Elliott,
Fiona Griffiths,
Wilna Oosthuyzen,
Kirstie Morrice,
Sean Keating,
Bo Wang,
Daniel Rhodes,
Lucija Klaric,
Marie Zechner,
Nick Parkinson,
Afshan Siddiq,
Peter Goddard,
Sally Donovan,
David Maslove,
Alistair Nichol,
Malcolm G. Semple,
Tala Zainy,
Fiona Maleady-Crowe,
Linda Todd,
Shahla Salehi,
Julian Knight,
Greg Elgar,
Georgia Chan,
Prabhu Arumugam,
Christine Patch,
Augusto Rendon,
David Bentley,
Clare Kingsley,
Jack A. Kosmicki,
Julie E. Horowitz,
Aris Baras,
Goncalo R. Abecasis,
Manuel A. R. Ferreira,
Anne Justice,
Tooraj Mirshahi,
Matthew Oetjens,
Daniel J. Rader,
Marylyn D. Ritchie,
Anurag Verma,
Tom A. Fowler,
Manu Shankar-Hari,
Charlotte Summers,
Charles Hinds,
Peter Horby,
Lowell Ling,
Danny McAuley,
Hugh Montgomery,
Peter J. M. Openshaw,
Paul Elliott,
Timothy Walsh,
Albert Tenesa,
Angie Fawkes,
Lee Murphy,
Kathy Rowan,
Chris P. Ponting,
Veronique Vitart,
James F. Wilson,
Jian Yang,
Andrew D. Bretherick,
Richard H. Scott,
Sara Clohisey Hendry,
Loukas Moutsianas,
Andy Law,
Mark J. Caulfield () and
J. Kenneth Baillie ()
Nature, 2022, vol. 607, issue 7917, 97-103 Abstract: Abstract Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 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 (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, 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. Date: 2022 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:607:y:2022:i:7917:d:10.1038_s41586-022-04576-6 Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-022-04576-6 Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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