Details

Autor(en) / Beteiligte

• Pairo-Castineira, Erola
• Rawlik, Konrad
• Bretherick, Andrew D
• Qi, Ting
• Wu, Yang
• Nassiri, Isar
• McConkey, Glenn A
• Zechner, Marie
• Klaric, Lucija
• Griffiths, Fiona
• Oosthuyzen, Wilna
• Kousathanas, Athanasios
• Richmond, Anne
• Millar, Jonathan
• Russell, Clark D
• Malinauskas, Tomas
• Thwaites, Ryan
• Morrice, Kirstie
• Keating, Sean
• Maslove, David
• Nichol, Alistair
• Semple, Malcolm G
• Knight, Julian
• Shankar-Hari, Manu
• Summers, Charlotte
• Hinds, Charles
• Horby, Peter
• Ling, Lowell
• McAuley, Danny
• Montgomery, Hugh
• Openshaw, Peter J M
• Begg, Colin
• Walsh, Timothy
• Tenesa, Albert
• Flores, Carlos
• Riancho, José A
• Rojas-Martinez, Augusto
• Lapunzina, Pablo
• Yang, Jian
• Ponting, Chris P
• Wilson, James F
• Vitart, Veronique
• Abedalthagafi, Malak
• Luchessi, Andre D
• Parra, Esteban J
• Cruz, Raquel
• Carracedo, Angel
• Fawkes, Angie
• Murphy, Lee
• Rowan, Kathy
• Pereira, Alexandre C
• Law, Andy
• Fairfax, Benjamin
• Hendry, Sara Clohisey
• Baillie, J Kenneth

Titel

GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19

Ist Teil von

• Nature (London), 2023-05, Vol.617 (7962), p.764-3

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2023

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown to be highly efficient for discovery of genetic associations . 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 group . 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).