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

description: Acknowledgements: We thank the patients who volunteered to all participating cohorts, and the researchers and clinicians who enrolled them into the respective studies. A full list of acknowledgments can be found in S1 and S2 Tables.
description: Funder: Lady Davis Institute of the Jewish General Hospital
description: Funder: Canadian Foundation for Innovation
description: Funder: NIH Foundation
description: Funder: Fonds de Recherche Québec Santé (FRQS)
description: Funder: McGill Interdisciplinary Initiative in Infection and Immunity (MI4)
description: Funder: Jewish General Hospital Foundation
description: Funder: Génome Québec; funder-id: http://dx.doi.org/10.13039/100013062
description: Funder: Public Health Agency of Canada
description: Funder: McGill University; funder-id: http://dx.doi.org/10.13039/100008582
description: Funder: Calcul Québec and Compute Canada
description: Funder: Compute Canada; funder-id: http://dx.doi.org/10.13039/100013020
description: Funder: Stiftung Universitätsmedizin Essen; funder-id: http://dx.doi.org/10.13039/501100010380
description: Funder: State of Saarland
description: Funder: Dr. Rolf M. Schwiete Foundation
description: Funder: Munich Clinician Scientist Programm
description: Funder: Netzwerk-Universitaetsmedizin-COVIM; Grant(s): NaFoUniMedCovid19, FKZ: 01KX2021
description: Funder: Federal Ministry of Education and Research
description: Funder: Leenaards Foundation
description: Funder: Santos-Suarez Foundation
description: Funder: Carigest
description: Funder: Istituto Buddista Italiano Soka Gakkai; Grant(s): 2020-2016_RIC_3 via project “PAT-COVID: Host genetics and pathogenetic mechanisms of COVID-19”
description: Funder: e-ASIA Joint Research Program (National Science and Technology Development Agency)
description: 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.