2024-03-29T06:40:17Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/161172023-07-18T07:07:46Zcom_20.500.12105_15322com_20.500.12105_2051com_20.500.12105_2060com_20.500.12105_2052col_20.500.12105_16988col_20.500.12105_16983col_20.500.12105_16981col_20.500.12105_16979col_20.500.12105_16978col_20.500.12105_16977col_20.500.12105_16976col_20.500.12105_16975col_20.500.12105_16973col_20.500.12105_16972col_20.500.12105_16971col_20.500.12105_16970col_20.500.12105_16967col_20.500.12105_16966col_20.500.12105_16964col_20.500.12105_16963col_20.500.12105_16962col_20.500.12105_16960col_20.500.12105_16959col_20.500.12105_16958col_20.500.12105_16938col_20.500.12105_2061
00925njm 22002777a 4500
dc
Pairo-Castineira, Erola
author
Rawlik, Konrad
author
Bretherick, Andrew D
author
Qi, Ting
author
Wu, Yang
author
Nassiri, Isar
author
McConkey, Glenn A
author
Zechner, Marie
author
Klaric, Lucija
author
Griffiths, Fiona
author
Oosthuyzen, Wilna
author
Kousathanas, Athanasios
author
Richmond, Anne
author
Millar, Jonathan
author
Russell, Clark D
author
Malinauskas, Tomas
author
Thwaites, Ryan
author
Morrice, Kirstie
author
Keating, Sean
author
Maslove, David
author
Nichol, Alistair
author
Semple, Malcolm G
author
Knight, Julian
author
Shankar-Hari, Manu
author
Summers, Charlotte
author
Hinds, Charles
author
Horby, Peter
author
Ling, Lowell
author
McAuley, Danny
author
Montgomery, Hugh
author
Openshaw, Peter J M
author
Begg, Colin
author
Walsh, Timothy
author
Tenesa, Albert
author
Flores, Carlos
author
Riancho, José A
author
Rojas-Martinez, Augusto
author
Lapunzina, Pablo
author
Yang, Jian
author
Ponting, Chris P
author
Wilson, James F
author
Vitart, Veronique
author
Abedalthagafi, Malak
author
Luchessi, Andre D
author
Parra, Esteban J
author
Cruz, Raquel
author
Carracedo, Angel
author
Fawkes, Angie
author
Murphy, Lee
author
Rowan, Kathy
author
Pereira, Alexandre C
author
Law, Andy
author
Fairfax, Benjamin
author
Hendry, Sara Clohisey
author
Baillie, J Kenneth
author
GenOMICC Investigators
author
SCOURGE Consortium
author
ISARICC Investigators
author
The 23andMe COVID-19 Team
author
Brochado-Kith, Oscar
author
Ceballos, Francisco C
author
Fernandez-Rodriguez, Amanda
author
Jimenez-Sousa, Maria Angeles
author
Martin-Vicente, Maria
author
Resino, Salvador
author
Virseda-Berdices, Ana
author
Meijome, Xose M
author
2023-05-17
Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).
Nature. 2023 May;617(7962):764-768.
http://hdl.handle.net/20.500.12105/16117
37198478
10.1038/s41586-023-06034-3
1476-4687
Nature
GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19