@article{Pairo-Castineira_E-2020_15304,
title = {Genetic mechanisms of critical illness in Covid-19},
author = {Pairo-Castineira, E. and Clohisey, S. and Klaric, L. and Bretherick, A. and Rawlik, K. and Pasko, D. and Walker, S. and Parkinson, N. and Head Fourman, M. and Russell, C. and Furniss, J. and Richmond, A. and Gountouna, E. and Wrobel, N. and Harrison, D. and Wang, B. and Wu, Y. and Meynert, A. and Griffiths, F. and Oosthuyzen, W. and Kousathanas, A. and Moutsianas, L. and Yang, Z. and Zhai, R. and Zheng, C. and Grimes, G. and Beale, R. and Millar, J. and Shih, B. and Keating, S. and Zechner, M. and Haley, C. and Porteous, D. and Hayward, C. and Yang, J. and Knight, J. and Summers, C. and Shankar-Hari, M. and Klenerman, P. and Turtle, L. and Ho, A. and Moore, S. and Hinds, C. and Horby, P. and Maslove, D. and Ling, L. and McAuley, D. and Montgomery, H. and Walsh, T. and Pereira, A. and Renieri, A. and The GenOMICC Investigators and ISARIC4C Investigators and The Covid-19 Human Genetics Initiative and 23andMe Investigators and BRACOVID Investigators and Gen-COVID Investigators and Shen, X. and Ponting, C. and Fawkes, A. and Tenesa, A. and Caulfield, M. and Scott, R. and Rowan, K. and Openshaw, P. and Semple, M. and Law, A. and Vitart, V. and Wilson, J. and Baillie, J.},
month = {dec},
year = {2020},
abstract = {Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study(GWAS) in 2244 critically ill Covid-19 patients from 208 UK intensive care units (ICUs). We identify and replicate novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 × 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 × 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 × 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 × 10-8) in the interferon receptor gene IFNAR2. We identify potential targets for repurposing of 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. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice.},
pages = {92-98},
volume = {591},
journal = {Nature},
publisher = {Springer Nature},
url = {http://dx.doi.org/10.1038/s41586-020-03065-y},
}
