Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
Guillaume Butler‐Laporte, Gundula Povysil, Jack A. Kosmicki, Elizabeth T. Cirulli, Theodore G. Drivas, Simone Furini, Chadi Saad, Axel Schmidt, Pawel Olszewski, Urszula Korotko, Mathieu Quinodoz, Elifnaz Çelik, Kousik Kundu, Klaudia Walter, Junghyun Jung, Amy Stockwell, Laura Sloofman, Daniel M. Jordan, Ryan C. Thompson, Diane M. Del Valle, Nicole W. Simons, Esther Cheng, Robert Sebra, Eric E. Schadt, Seunghee Kim‐Schulze, Sacha Gnjatic, Miriam Mérad, Joseph D. Buxbaum, Noam D. Beckmann, Alexander W. Charney, Bartlomiej Przychodzen, Timothy S. Chang, Tess D. Pottinger, Ning Shang, Fabian Brand, Francesca Fava, Francesca Mari, Karolina Chwiałkowska, Magdalena Niemira, Szymon Puła, J. Kenneth Baillie, Alexander 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 Eveleigh, Vincenzo Forgetta, David Morrison, David Langlais, Mark Lathrop, Vincent Mooser, Tomoko Nakanishi, Robert Frithiof, Michael Hultström, Miklós 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 Almutairi, Yaseen M. Arabi, Saleh A. Alqahtani, Fawz S. Al Harthi, Amal Almutairi, Fatima Alqubaishi, Sarah Alotaibi, Albandari Binowayn, Ebtehal Alsolm, Hadeel El Bardisy, Mohammad Fawzy, Fang Cai, Nicole Soranzo, Adam S. Butterworth, COVID-19 Host Genetics Initiative, DeCOI Host Genetics Group, Japan COVID-19 Task Force, Daniel H. Geschwind, Stephanie A. Arteaga, Alexis Stephens, Manish J. Butte
Abstract
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.