Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals

Kosmicki, J. A.; Horowitz, J. E.; Banerjee, N.; Lanche, R.; Marcketta, A.; Maxwell, E.; Bai, X. D.; Sun, D.; Backman, J. D.; Sharma, D.; Kury, F. S. P.; Kang, H. M.; O039,; Dushlaine, C.; Yadav, A.; Mansfield, A. J.; Li, A. H.; Watanabe, K.; Gurski, L.; McCarthy, S. E.; Locke, A. E.; Khalid, S.; Keeffe, S.; Mbatchou, J.; Chazara, O.; Huang, Y. F.; Kvikstad, E.; Neill, A.; Nioi, P.; Parker, M. M.; Petrovski, S.; Runz, H.; Szustakowski, J. D.; Wang, Q. L.; Wong, E.; Cordova-Palomera, A.; Smith, E. N.; Szalma, S.; Zheng, X. W.; Esmaeeli, S.; Davis, J. W.; Lai, Y. P.; Chen, X.; Justice, A. E.; Leader, J. B.; Mirshahi, T.; Carey, D. J.; Verma, A.; Sirugo, G.; Ritchie, M. D.; Rader, D. J.; Povysil, G.; Goldstein, D. B.; Kiryluk, K.; Pairo-Castineira, E.; Rawlik, K.; Pasko, D.; Walker, S.; Meynert, A.; Kousathanas, A.; Moutsianas, L.; Tenesa, A.; Caulfield, M.; Scott, R.; Wilson, J. F.; Baillie, J. K.; Butler-Laporte, G.; Nakanishi, T.; Lathrop, M.; Richards, J. B.; Jones, M.; Balasubramanian, S.; Salerno, W.; Shuldiner, A. R.; Marchini, J.; Overton, J. D.; Habegger, L.; Cantor, M. N.; Reid, J. G.; Baras, A.; Abecasis, G. R.; Ferreira, M. A. R.; Regeneron Genetics, Ctr Consortium U. K. B. Exome Sequencing; Kosmicki, Jack A.; Horowitz, Julie E.; Banerjee, Nilanjana Lanche Rouel Marcketta Anthony Maxwell Evan Bai Xiaodong Sun Dylan Backman Joshua D.; Sharma, Deepika Kury Fabricio S. P.; Kang, Hyun M.; O’Dushlaine, Colm Yadav Ashish Mansfield Adam J.; Li, Alexander H.; Watanabe, Kyoko Gurski Lauren McCarthy Shane E.; Locke, Adam E.; Khalid, Shareef O’Keeffe Sean Mbatchou Joelle Chazara Olympe Huang Yunfeng Kvikstad Erika O’Neill Amanda Nioi Paul Parker Meg M.; Petrovski, Slavé Runz Heiko Szustakowski Jospeh D.; Wang, Quanli Wong Emily Cordova-Palomera Aldo Smith Erin N.; Szalma, Sandor Zheng Xiuwen Esmaeeli Sahar Davis Justin W.; Lai, Yi-Pin Chen Xing Justice Ann E.; Leader, Joseph B.; Mirshahi, Tooraj Carey David J.; Verma, Anurag Sirugo Giorgio Ritchie Marylyn D.; Rader, Daniel J.; Povysil, Gundula Goldstein David B.; Kiryluk, Krzysztof Pairo-Castineira Erola Rawlik Konrad Pasko Dorota Walker Susan Meynert Alison Kousathanas Athanasios Moutsianas Loukas Tenesa Albert Caulfield Mark Scott Richard Wilson James F.; Baillie, J. Kenneth Butler-Laporte Guillaume Nakanishi Tomoko Lathrop Mark Richards J. Brent Jones Marcus Balasubramanian Suganthi Salerno William Shuldiner Alan R.; Marchini, Jonathan Overton John D.; Habegger, Lukas Cantor Michael N.; Reid, Jeffrey G.; Baras, Aris Abecasis Goncalo R.; Ferreira, Manuel A. R.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, and results are publicly available through the Regeneron Genetics Center COVID-19 Results Browser.