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Título: | GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19 |
Fecha de publicación: | 17-may-2023 |
Editorial: | Springer Nature |
Cita bibliográfica: | Nature (2023), 617:764–768 |
ISSN: | Print: 0028-0836 Electronic: 1476-4687 |
Resumen: | 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). |
Autor/es principal/es: | 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 Milla, Jonathan Russel, Clark D. Malinauskas, Tomas Thwaites, Ryan Morrice, Kirstie Keating, Sean Maslove, David Nicho, Alistair Semple, Malcolm G. Knigh, 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 GenOMICC Investigators SCOURGE Consortium ISARICC Investigators The 23andMe COVID-19 Team Yang, Jian Ponting, Chris Wilson, James F. Vitart, Veronique Abedalthagaf, Malak Luchess, Andre D. Parra, Esteban J. Cruz, Raquel Carracedo, Ángel Fawkes, Angie Murphy, Lee Rowan, Kathy Pereira, Alexandre C. Law, Andy Fairfax, Benjamin Clohisey Hendry, Sara Kenneth Baillie, J. |
Facultad/Departamentos/Servicios: | Facultades, Departamentos, Servicios y Escuelas::Departamentos de la UMU::Medicina Interna |
Versión del editor: | https://www.nature.com/articles/s41586-023-06034-3 |
URI: | http://hdl.handle.net/10201/142728 |
DOI: | https://doi.org/10.1038s41586-023-06034-3 |
Tipo de documento: | info:eu-repo/semantics/article |
Número páginas / Extensión: | 5 |
Derechos: | info:eu-repo/semantics/embargoedAccess |
Descripción: | ©2023 The Author(s). This manuscript version is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/. This document is the Published, version of a Published Work that appeared in final form in Nature. To access the final edited and published work see https://doi.org/10.1038s41586-023-06034-3 |
Aparece en las colecciones: | Artículos: Medicina |
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