GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
Erola Pairo‐Castineira, Konrad Rawlik, Andrew D. Bretherick, Ting Qi, Yang Wu, Isar Nassiri, Glenn A. McConkey, Marie Zechner, Lucija Klarić, Fiona Griffiths, Wilna Oosthuyzen, Athanasios Kousathanas, Anne Richmond, Jonathan Millar, Clark D Russell, Tomas Malinauskas, Ryan S. Thwaites, Kirstie Morrice, Seán Keating, David M. Maslove, Alistair Nichol, Malcolm G. Semple, Julian C. Knight, Manu Shankar‐Hari, Charlotte Summers, Charles Hinds, Peter Horby, Lowell Ling, Daniel F. McAuley, Hugh Montgomery, Peter Openshaw, Colin B. Begg, Timothy Walsh, Albert Tenesa, Carlos Flores, José A. Riancho, Augusto Rojas‐Martínez, Pablo Lapunzina, GenOMICC Investigators, Co-Investigators, Sara Clohisey, Johnny Millar, Manu Shankar‐Hari, Emma Aitkin, Latha Aravindan, Ruth Armstrong, J. Kenneth Baillie, Heather Biggs, Ceilia Boz, Adam Brown, Primmy Chikowore, Richard Clark, Audrey Coutts, J. Terrence Coyle, Louise Cullum, Sukamal Das, Nicky Day, Lorna Donnelly, Esther Duncan, Paul Finernan, Max Head Fourman, Anita Furlong, James Furniss, Bernadette Gallagher, Tammy Gilchrist, Ailsa Golightly, Fiona Griffiths, Katarzyna Hafezi, Debbie Hamilton, Ross Hendry, Naomi Kearns, Dawn Law, R. M. Law, Sarah Law, Rebecca Lidstone-Scott, Christen Lauder, Louise MacGillivray, Alan Maclean, Hanning Mal, Sarah McCafferty, Ellie Mcmaster, Jen Meikle, Shona C. Moore, Sheena Murphy, Hellen Mybaya, Miranda Odam, Wilna Oosthuyzen, Chenqing Zheng, Jiantao Chen, Nick Parkinson, Trevor Paterson, Petra Tucker, Katherine Schon, Andrew Stenhouse, Mihaela Das, Maaike Swets, Helen Szoor-McElhinney, Filip Taneski, Lance Turtle, Tony Wackett
Abstract
Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . 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 3 . 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 ).