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 Junghyung , Stockwell Amy D , Sloofman Laura G , Jordan Daniel M. , Thompson Ryan C. , Valle Diane Del , Simons Nicole , Cheng Esther , Sebra Robert , Schadt Eric E. , Schulze-Kim 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. , Alqahtan Saleh A. , Harthi Fawz S. Al , Almutairi Amal , Alqubaishi Fatima , Alotaibi Sarah , Binowayn Albandari , Alsolm Ebtehal A. , Bardisy Hadeel El , Fawzy Mohammad ,   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 Katsuhi , 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: April 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=5.41×10−7). 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.

Author Summary

COVID-19 clinical outcomes vary immensely, but a patient’s genetic make-up is an important determinant of how they will fare against the virus. While many genetic variants commonly found in the populations were previously found to be contributing to more severe disease by the COVID-19 Host Genetics Initiative, it isn’t clear if more rare variants found in less individuals could also play a role. This is important because genetic variants with the largest impact on COVID-19 severity are expected to be rarely found in the population, and these rare variants require different technologies to be studies (usually whole-exome or whole-genome sequencing). Here, we combined sequencing results from 21 cohorts across 12 countries to perform a rare variant association study. In an analysis comprising 5,085 participants with severe COVID-19 and 571,737 controls, we found that the gene for toll-like receptor 7 (TLR7) on chromosome X was an important determinant of severe COVID-19. Importantly, despite being found on a sex chromosome, this observation was consistent across both sexes.