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

by Guillaume Butler-Laporte, Gundula Povysil, Jack A. Kosmicki, Elizabeth T. Cirulli, Theodore Drivas, Simone Furini, Chadi Saad, Axel Schmidt, Pawel Olszewski, Urszula Korotko, Mathieu Quinodoz, Elifnaz Çelik, Kousik Kundu, Klaudia Walter, Junghyun Jung, Amy D. Stockwell, Laura G. Sloofman, Daniel M. Jordan, Ryan C. Thompson, Diane Del Valle, Nicole Simons, Esther Cheng, Robert Sebra, Eric E. Schadt, Seunghee Kim-Schulze, Sacha Gnjatic, Miriam Merad, Joseph D. Buxbaum, Noam D. Beckmann, Alexander W. Charney, Bartlomiej Przychodzen, Timothy Chang, Tess D. Pottinger, Ning Shang, Fabian Brand, Francesca Fava, Francesca Mari, Karolina Chwialkowska, Magdalena Niemira, Szymon Pula, J Kenneth Baillie, Alex Stuckey, Antonio Salas, Xabier Bello, Jacobo Pardo-Seco, Alberto Gómez-Carballa, Irene Rivero-Calle, Federico Martinón-Torres, Andrea Ganna, Konrad J. Karczewski, Kumar Veerapen, Mathieu Bourgey, Guillaume Bourque, Robert JM Eveleigh, Vincenzo Forgetta, David Morrison, David Langlais, Mark Lathrop, Vincent Mooser, Tomoko Nakanishi, Robert Frithiof, Michael Hultström, Miklos Lipcsey, Yanara Marincevic-Zuniga, Jessica Nordlund, Kelly M. Schiabor Barrett, William Lee, Alexandre Bolze, Simon White, Stephen Riffle, Francisco Tanudjaja, Efren Sandoval, Iva Neveux, Shaun Dabe, Nicolas Casadei, Susanne Motameny, Manal Alaamery, Salam Massadeh, Nora Aljawini, Mansour S. Almutairi, Yaseen M. Arabi, Saleh A. Alqahtani, Fawz S. Al Harthi, Amal Almutairi, Fatima Alqubaishi, Sarah Alotaibi, Albandari Binowayn, Ebtehal A. Alsolm, Hadeel El Bardisy, Mohammad Fawzy, Fang Cai, Nicole Soranzo, Adam Butterworth, COVID-19 Host Genetics Initiative , DeCOI Host Genetics Group , GEN-COVID Multicenter Study (Italy) , Mount Sinai Clinical Intelligence Center , GEN-COVID consortium (Spain) , GenOMICC Consortium , Japan COVID-19 Task Force , Regeneron Genetics Center , Daniel H. Geschwind, Stephanie Arteaga, Alexis Stephens, Manish J. Butte, Paul C. Boutros, Takafumi N. Yamaguchi, Shu Tao, Stefan Eng, Timothy Sanders, Paul J. Tung, Michael E. Broudy, Yu Pan, Alfredo Gonzalez, Nikhil Chavan, Ruth Johnson, Bogdan Pasaniuc, Brian Yaspan, Sandra Smieszek, Carlo Rivolta, Stephanie Bibert, Pierre-Yves Bochud, Maciej Dabrowski, Pawel Zawadzki, Mateusz Sypniewski, Elżbieta Kaja, Pajaree Chariyavilaskul, Voraphoj Nilaratanakul, Nattiya Hirankarn, Vorasuk Shotelersuk, Monnat Pongpanich, Chureerat Phokaew, Wanna Chetruengchai, Katsushi Tokunaga, Masaya Sugiyama, Yosuke Kawai, Takanori Hasegawa, Tatsuhiko Naito, Ho Namkoong, Ryuya Edahiro, Akinori Kimura, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga, Yukinori Okada, Seiya Imoto, Satoru Miyano, Serghei Mangul, Malak S. Abedalthagafi, Hugo Zeberg, Joseph J. Grzymski, Nicole L. Washington, Stephan Ossowski, Kerstin U. Ludwig, Eva C. Schulte, Olaf Riess, Marcin Moniuszko, Miroslaw Kwasniewski, Hamdi Mbarek, Said I. Ismail, Anurag Verma, David B. Goldstein, Krzysztof Kiryluk, Alessandra Renieri, Manuel A. R. Ferreira, J Brent Richards

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 5,085 severe disease cases and 571,737 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 = 5.41x10^-7). This association was consistent across sexes. 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.