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@article{Pairo-Castineira:2023:10.1038/s41586-023-06034-3,
author = {Pairo-Castineira, E and Rawlik, K and Bretherick, AD and Qi, T and Wu, Y and Nassiri, I and McConkey, GA and Zechner, M and Klaric, L and Griffiths, F and Oosthuyzen, W and Kousathanas, A and Richmond, A and Millar, J and Russell, CD and Malinauskas, T and Thwaites, R and Morrice, K and Keating, S and Maslove, D and Nichol, A and Semple, MG and Knight, J and Shankar-Hari, M and Summers, C and Hinds, C and Horby, P and Ling, L and McAuley, D and Montgomery, H and Openshaw, PJM and Begg, C and Walsh, T and Tenesa, A and Flores, C and Riancho, JA and Rojas-Martinez, A and Lapunzina, P and GenOMICC, Investigators and SCOURGE, Consortium and ISARICC, Investigators and 23andMe, COVID-19 Team and Yang, J and Ponting, CP and Wilson, JF and Vitart, V and Abedalthagafi, M and Luchessi, AD and Parra, EJ and Cruz, R and Carracedo, A and Fawkes, A and Murphy, L and Rowan, K and Pereira, AC and Law, A and Fairfax, B and Hendry, SC and Baillie, JK},
doi = {10.1038/s41586-023-06034-3},
journal = {Nature},
pages = {764--768},
title = {GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19},
url = {http://dx.doi.org/10.1038/s41586-023-06034-3},
volume = {617},
year = {2023}
}

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TY  - JOUR
AB  - 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).
AU  - Pairo-Castineira,E
AU  - Rawlik,K
AU  - Bretherick,AD
AU  - Qi,T
AU  - Wu,Y
AU  - Nassiri,I
AU  - McConkey,GA
AU  - Zechner,M
AU  - Klaric,L
AU  - Griffiths,F
AU  - Oosthuyzen,W
AU  - Kousathanas,A
AU  - Richmond,A
AU  - Millar,J
AU  - Russell,CD
AU  - Malinauskas,T
AU  - Thwaites,R
AU  - Morrice,K
AU  - Keating,S
AU  - Maslove,D
AU  - Nichol,A
AU  - Semple,MG
AU  - Knight,J
AU  - Shankar-Hari,M
AU  - Summers,C
AU  - Hinds,C
AU  - Horby,P
AU  - Ling,L
AU  - McAuley,D
AU  - Montgomery,H
AU  - Openshaw,PJM
AU  - Begg,C
AU  - Walsh,T
AU  - Tenesa,A
AU  - Flores,C
AU  - Riancho,JA
AU  - Rojas-Martinez,A
AU  - Lapunzina,P
AU  - GenOMICC,Investigators
AU  - SCOURGE,Consortium
AU  - ISARICC,Investigators
AU  - 23andMe,COVID-19 Team
AU  - Yang,J
AU  - Ponting,CP
AU  - Wilson,JF
AU  - Vitart,V
AU  - Abedalthagafi,M
AU  - Luchessi,AD
AU  - Parra,EJ
AU  - Cruz,R
AU  - Carracedo,A
AU  - Fawkes,A
AU  - Murphy,L
AU  - Rowan,K
AU  - Pereira,AC
AU  - Law,A
AU  - Fairfax,B
AU  - Hendry,SC
AU  - Baillie,JK
DO  - 10.1038/s41586-023-06034-3
EP  - 768
PY  - 2023///
SN  - 0028-0836
SP  - 764
TI  - GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
T2  - Nature
UR  - http://dx.doi.org/10.1038/s41586-023-06034-3
UR  - https://www.ncbi.nlm.nih.gov/pubmed/37198478
UR  - https://www.nature.com/articles/s41586-023-06034-3
UR  - http://hdl.handle.net/10044/1/104327
VL  - 617
ER  -

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Peter Openshaw - Professor of Experimental Medicine

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