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

Publication

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

Journal Paper/Review - Mar 7, 2022

Kousathanas Athanasios, Pairo-Castineira Erola, Rawlik Konrad, Stuckey Alex, Odhams Christopher A, Walker Susan, Russell Clark D, Malinauskas Tomas, Wu Yang, Millar Jonathan, Shen Xia, Elliott Katherine S, Griffiths Fiona, Oosthuyzen Wilna, Morrice Kirstie, Keating Sean, Wang Bo, Rhodes Daniel, Klaric Lucija, Zechner Marie, Parkinson Nick, Siddiq Afshan, Goddard Peter, Donovan Sally, Maslove David, Nichol Alistair D, Semple Malcolm G, Zainy Tala, Maleady-Crowe Fiona, Todd Linda, Salehi Shahla, Knight Julian, Elgar Greg, Chan Georgia, Arumugam Prabhu, Patch Christine, Rendon Augusto, Bentley David, Kingsley Clare, Kosmicki Jack A, Horowitz Julie E, Baras Aris, Abecasis Gonçalo R, Ferreira Manuel A R, Justice Anne E, Mirshahi Tooraj, Oetjens Matthew, Rader Daniel J, Ritchie Marylyn D, Verma Anurag, Fowler Tom A, Shankar-Hari Manu, Summers Charlotte, Hinds Charles, Horby Peter, Ling Lowell, McAuley Danny, Montgomery Hugh, Openshaw Peter J M, Elliott Paul, Walsh Timothy, Tenesa Albert, Fawkes Angie, Murphy Lee, Rowan Kathy, Ponting Chris P, Vitart Veronique, Wilson James F, Yang Jian, Bretherick Andrew D, Scott Richard H, Hendry Sara Clohisey, Moutsianas Loukas, Law Andy, Caulfield Mark J, Baillie J Kenneth, Albrich Werner

Citation

Kousathanas A, Pairo-Castineira E, Rawlik K, Stuckey A, Odhams C, Walker S, Russell C, Malinauskas T, Wu Y, Millar J, Shen X, Elliott K, Griffiths F, Oosthuyzen W, Morrice K, Keating S, Wang B, Rhodes D, Klaric L, Zechner M, Parkinson N, Siddiq A, Goddard P, Donovan S, Maslove D, Nichol A, Semple M, Zainy T, Maleady-Crowe F, Todd L, Salehi S, Knight J, Elgar G, Chan G, Arumugam P, Patch C, Rendon A, Bentley D, Kingsley C, Kosmicki J, Horowitz J, Baras A, Abecasis G, Ferreira M, Justice A, Mirshahi T, Oetjens M, Rader D, Ritchie M, Verma A, Fowler T, Shankar-Hari M, Summers C, Hinds C, Horby P, Ling L, McAuley D, Montgomery H, Openshaw P, Elliott P, Walsh T, Tenesa A, Fawkes A, Murphy L, Rowan K, Ponting C, Vitart V, Wilson J, Yang J, Bretherick A, Scott R, Hendry S, Moutsianas L, Law A, Caulfield M, Baillie J, Albrich W. Whole-genome sequencing reveals host factors underlying critical COVID-19. Nature 2022; 607:97-103.

Type

Journal Paper/Review (English)

Journal

Nature 2022; 607

Publication Date

Mar 7, 2022

Issn Electronic

1476-4687

Pages

97-103

Brief description/objective

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization 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.