E. Pairo-Castineira, S. Clohisey, L. Klarić, A. Bretherick, K. Rawlik, N. Parkinson, D. Pasko, Susan Walker, A. Richmond, M. Fourman, Clark D Russell, A. Law, James J Furniss, Elvina Gountouna, N. Wrobel, L. Moutsianas, Bo Wang, A. Meynert, Zhijian Yang, R. Zhai, Chenqing Zheng, F. Griffiths, W. Oosthuyzen, G. Grimes, Barbara B Shih, S. Keating, M. Zechner, C. Haley, David J. Porteous, C. Hayward, Julian Knight, C. Summers, M. Shankar-Hari, P. Klenerman, L. Turtle, Antonia Ho, C. Hinds, P. Horby, A. Nichol, D. Maslove, Lowell Ling, D. McAuley, H. Montgomery, T. Walsh, Xia Shen, K. Rowan, A. Fawkes, L. Murphy, C. Ponting, A. Tenesa, M. Caulfield, Richard Scott, P. Openshaw, M. Semple, V. Vitart, James F. Wilson, J. K. Baillie
medRxiv, 2020
The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases. Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19. GenOMICC (Genetics Of Mortality In Critical Care, genomicc.org) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2790 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing >95% of all ICU beds. Random controls were drawn from three distinct UK population studies. We identify and replicate several novel genome-wide significant associations including variants chr19p13.3 (rs2109069, P = 3.98 x 10-12), within the gene encoding dipeptidyl peptidase 9 (DPP9), and at chr21q22.1 (rs2236757, P = 4.99 x 10-8) in the interferon receptor IFNAR2. Consistent with our focus on extreme disease in younger patients with less comorbidity, we detect a stronger signal at the known 3p21.31 locus than previous studies (rs73064425, P = 1.2 x 10-27). We identify potential targets for repurposing of existing licensed medications. Using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease. Transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. We detected genome-wide significant gene-level associations for genes with central roles in viral restriction (OAS1, OAS2, OAS3). These results identify specific loci associated with life-threatening disease, and potential targets for host-directed therapies. Randomised clinical trials will be necessary before any change to clinical practice.
Cited by 227 publications.
Field of study: Medicine