Publication

Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

G. Butler-Laporte, G. Povysil, J. Kosmicki, E. T. Cirulli, T. Drivas, S. Furini, C. Saad, A. Schmidt, P. Olszewski, U. Korotko, M. Quinodoz, E. Celik, K. Kundu, K. Walter, J. Jung, A. D. Stockwell, L. G. Sloofman, A. W. Charney, D. Jordan, N. Beckmann, B. Przychodzen, T. Chang, T. D. Pottinger, N. Shang, F. Brand, F. Fava, F. Mari, K. Chwialkowska, M. Niemira, S. Pula, J. K. Baillie, A. Stuckey, A. Gann, K. J. Karczewski, K. Veerapen, M. Bourgey, G. Bourque, R. JM. Eveleigh, V. Forgetta, D. Morrison, D. Langlais, M. Lathrop, V. Mooser, T. Nakanishi, R. Frithof, M. Hulström, M. Lipcsey, Y. Marincevic-Zuniga, J. Nordlund, K. M. S. Barret, W. Lee, A. Bolze, S. White, S. Riffle, F. Tanudjaja, E. Sandoval, I. Neveux, S. Dabe, N. Casadei, S. Motameny, M. Alaamery, S. Massadeh, N. Aljawani, M. S. Almutairi, Y. M. Arabi, S. A. Alqahtan, F. S. A. Harthi, A. Almutairi, F. Alqubaishi, S. Alotaibi, A. Binowayn, E. A. Alsolm, H. E. Bardisy, M. Fawzy, COVID-19 Host Genetics Initiative, DeCOI Host Genetics Group, GEN-COVID Multicenter Study, GenOMICC Consortium, Japan COVID-19 Task Force, Regeneron Genetics Center, D. H. Geschwind, S. Arteaga, A. Stephens, M. J. Butte, P. C. Boutros, T. N. Yamaguchi, S. Tao, S. Eng, T. Sanders, P. J. Tung, M. E. Broudy, Y. Pan, A. Gonzalez, N. Chavan, R. Johnson, B. Pasaniuc, B. Yaspan, S. Smieszek, C. Rivolta, S. Bibert, P. Bochud, M. Dabrowski, P. Zawadzki, M. Sypniewski, E. Kaja, P. Chariyavilaskul, V. Nilaratanakul, N. Hirankarn, V. Shotelersuk, M. Pongpanich, C. Phokaew, W. Chetruengchai, Y. Kawai, T. Hasegawa, T. Naito, H. Namkoong, R. Edahiro, A. Kimura, S. Ogawa, T. Kanai, K. Fukunaga, Y. Okada, S. Imoto, S. Miyano, S. Mangul, M. S. Abedalthagafi, H. Zeberg, J. J. Grzymski, N. L. Washingto, S. Ossowki, K. Ludwig, E. C. Schulte, O. Riess, M. Moniuszko, M. Kwasniewski, H. Mbarek, S. I. Ismali, A. Verma, D. B. Goldstein, K. Kiryluk, A. Renieri, M. Ferreira, J. B. Richards

Published
March 31, 2022
journal
Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes.

However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,048 severe disease cases and 571,009 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p=5.41×10-7). These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
June 22, 2022