학술논문
Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
Document Type
Author
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, 1978; Lipcsey, Miklós; 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; 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
Source
PLOS Genetics. 18(11)
Subject
Language
English
ISSN
1553-7390
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.