Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
Authors: Butler-Laporte Guillaume , Povysil Gundula , Kosmicki Jack A. , Cirulli Elizabeth T. , Drivas Theodore , Furini Simone , Saad Chadi , Schmidt Axel , Olszewski Pawel , Korotko Urszula , Quinodoz Mathieu , Çelik Elifnaz , Kundu Kousik , Walter Klaudia , Jung Junghyun , Stockwell Amy D. , Sloofman Laura G. , Jordan Daniel M. , Thompson Ryan C. , Del Valle Diane , Simons Nicole , Cheng Esther , Sebra Robert , Schadt Eric E. , Kim-Schulze Seunghee , Gnjatic Sacha , Merad Miriam , Buxbaum Joseph D. , Beckmann Noam D. , Charney Alexander W. , Przychodzen Bartlomiej , Chang Timothy , Pottinger Tess D. , Shang Ning , Brand Fabian , Fava Francesca , Mari Francesca , Chwialkowska Karolina , Niemira Magdalena , Pula Szymon , Baillie J Kenneth , Stuckey Alex , Salas Antonio , Bello Xabier , Pardo-Seco Jacobo , Gómez-Carballa Alberto , Rivero-Calle Irene , Martinón-Torres Federico , Ganna Andrea , Karczewski Konrad J. , Veerapen Kumar , Bourgey Mathieu , Bourque Guillaume , Eveleigh Robert JM , Forgetta Vincenzo , Morrison David , Langlais David , Lathrop Mark , Mooser Vincent , Nakanishi Tomoko , Frithiof Robert , Hultström Michael , Lipcsey Miklos , Marincevic-Zuniga Yanara , Nordlund Jessica , Schiabor Barrett Kelly M. , Lee William , Bolze Alexandre , White Simon , Riffle Stephen , Tanudjaja Francisco , Sandoval Efren , Neveux Iva , Dabe Shaun , Casadei Nicolas , Motameny Susanne , Alaamery Manal , Massadeh Salam , Aljawini Nora , Almutairi Mansour S. , Arabi Yaseen M. , Alqahtani Saleh A. , Al Harthi Fawz S. , Almutairi Amal , Alqubaishi Fatima , Alotaibi Sarah , Binowayn Albandari , Alsolm Ebtehal A. , El Bardisy Hadeel , Fawzy Mohammad , Cai Fang , Soranzo Nicole , Butterworth Adam ,   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, Geschwind Daniel H. , Arteaga Stephanie , Stephens Alexis , Butte Manish J. , Boutros Paul C. , Yamaguchi Takafumi N. , Tao Shu , Eng Stefan , Sanders Timothy , Tung Paul J. , Broudy Michael E. , Pan Yu , Gonzalez Alfredo , Chavan Nikhil , Johnson Ruth , Pasaniuc Bogdan , Yaspan Brian , Smieszek Sandra , Rivolta Carlo , Bibert Stephanie , Bochud Pierre-Yves , Dabrowski Maciej , Zawadzki Pawel , Sypniewski Mateusz , Kaja Elżbieta , Chariyavilaskul Pajaree , Nilaratanakul Voraphoj , Hirankarn Nattiya , Shotelersuk Vorasuk , Pongpanich Monnat , Phokaew Chureerat , Chetruengchai Wanna , Tokunaga Katsushi , Sugiyama Masaya , Kawai Yosuke , Hasegawa Takanori , Naito Tatsuhiko , Namkoong Ho , Edahiro Ryuya , Kimura Akinori , Ogawa Seishi , Kanai Takanori , Fukunaga Koichi , Okada Yukinori , Imoto Seiya , Miyano Satoru , Mangul Serghei , Abedalthagafi Malak S. , Zeberg Hugo , Grzymski Joseph J. , Washington Nicole L. , Ossowski Stephan , Ludwig Kerstin U. , Schulte Eva C. , Riess Olaf , Moniuszko Marcin , Kwasniewski Miroslaw , Mbarek Hamdi , Ismail Said I. , Verma Anurag , Goldstein David B. , Kiryluk Krzysztof , Renieri Alessandra , Ferreira Manuel A. R. , Richards J Brent 
Published: November 2022

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.