1. Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
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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 AR, Richards, J Brent, Butler-Laporte, Guillaume [0000-0001-5388-0396], Povysil, Gundula [0000-0003-4625-5909], Kosmicki, Jack A [0000-0003-1252-6192], Cirulli, Elizabeth T [0000-0001-7808-2809], Drivas, Theodore [0000-0002-8717-0111], Saad, Chadi [0000-0001-6963-9126], Olszewski, Pawel [0000-0003-1010-8843], Korotko, Urszula [0000-0002-1779-8368], Quinodoz, Mathieu [0000-0002-9841-4433], Çelik, Elifnaz [0000-0002-0324-5228], Kundu, Kousik [0000-0002-1019-8351], Walter, Klaudia [0000-0003-4448-0301], Sloofman, Laura G [0000-0001-7628-4378], Jordan, Daniel M [0000-0002-5318-8225], Thompson, Ryan C [0000-0002-0450-8181], Del Valle, Diane [0000-0001-6983-5362], Simons, Nicole [0000-0002-3952-1458], Chang, Timothy [0000-0002-9225-9874], Brand, Fabian [0000-0003-1885-7021], Chwialkowska, Karolina [0000-0001-8053-8959], Niemira, Magdalena [0000-0002-0701-4961], Pula, Szymon [0000-0002-5684-5358], Stuckey, Alex [0000-0001-8636-737X], Bello, Xabier [0000-0002-4990-8496], Karczewski, Konrad J [0000-0003-2878-4671], Bourgey, Mathieu [0000-0002-8432-834X], Bourque, Guillaume [0000-0002-3933-9656], Eveleigh, Robert Jm [0000-0002-4147-382X], Morrison, David [0000-0001-8380-3615], Langlais, David [0000-0003-4429-0110], Mooser, Vincent [0000-0002-8632-0448], Nakanishi, Tomoko [0000-0001-9510-5646], Frithiof, Robert [0000-0003-2278-7951], Hultström, Michael [0000-0003-4675-1099], Lipcsey, Miklos [0000-0002-1976-4129], Nordlund, Jessica [0000-0001-8699-9959], Schiabor Barrett, Kelly M [0000-0001-6194-787X], Bolze, Alexandre [0000-0001-7399-2766], White, Simon [0000-0001-6375-2363], Dabe, Shaun [0000-0002-2494-962X], Casadei, Nicolas [0000-0003-2209-0580], Motameny, Susanne [0000-0003-1186-1108], Massadeh, Salam [0000-0001-9193-0008], Almutairi, Mansour S [0000-0003-2736-8991], Arabi, Yaseen M [0000-0001-5735-6241], Fawzy, Mohammad [0000-0002-1318-9979], Arteaga, Stephanie [0000-0003-1441-8849], Stephens, Alexis [0000-0002-5979-6838], Yamaguchi, Takafumi N [0000-0003-1082-3871], Eng, Stefan [0000-0002-5245-6507], Gonzalez, Alfredo [0000-0001-8963-3135], Johnson, Ruth [0000-0002-1929-0998], Yaspan, Brian [0000-0002-3787-2510], Smieszek, Sandra [0000-0002-8006-0454], Rivolta, Carlo [0000-0002-0733-9950], Bochud, Pierre-Yves [0000-0002-2208-4757], Dabrowski, Maciej [0000-0003-4150-3985], Zawadzki, Pawel [0000-0002-9032-2315], Kaja, Elżbieta [0000-0003-1277-6140], Chariyavilaskul, Pajaree [0000-0003-1096-6020], Nilaratanakul, Voraphoj [0000-0002-3964-5477], Hirankarn, Nattiya [0000-0003-2224-6856], Shotelersuk, Vorasuk [0000-0002-1856-0589], Pongpanich, Monnat [0000-0003-3228-3351], Phokaew, Chureerat [0000-0002-4246-2604], Chetruengchai, Wanna [0000-0003-2495-6595], Sugiyama, Masaya [0000-0002-9084-7197], Kawai, Yosuke [0000-0003-0666-1224], Hasegawa, Takanori [0000-0001-7251-9950], Namkoong, Ho [0000-0001-6181-4284], Miyano, Satoru [0000-0002-1753-6616], Mangul, Serghei [0000-0003-4770-3443], Zeberg, Hugo [0000-0001-7118-1249], Grzymski, Joseph J [0000-0003-2646-8958], Ossowski, Stephan [0000-0002-7416-9568], Ludwig, Kerstin U [0000-0002-8541-2519], Schulte, Eva C [0000-0003-3105-5672], Verma, Anurag [0000-0002-5063-9107], Goldstein, David B [0000-0001-7627-0259], Kiryluk, Krzysztof [0000-0002-5047-6715], Renieri, Alessandra [0000-0002-0846-9220], Richards, J Brent [0000-0002-3746-9086], and Apollo - University of Cambridge Repository
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Medicine and health sciences ,Research and analysis methods ,Physical sciences ,Toll-Like Receptor 7 ,Biology and life sciences ,SARS-CoV-2 ,FOS: Physical sciences ,Humans ,COVID-19 ,Exome ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Research Article - Abstract
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., Funder: Lady Davis Institute of the Jewish General Hospital, Funder: Canadian Foundation for Innovation, Funder: NIH Foundation, Funder: Fonds de Recherche Québec Santé (FRQS), Funder: McGill Interdisciplinary Initiative in Infection and Immunity (MI4), Funder: Jewish General Hospital Foundation, Funder: Génome Québec; funder-id: http://dx.doi.org/10.13039/100013062, Funder: Public Health Agency of Canada, Funder: McGill University; funder-id: http://dx.doi.org/10.13039/100008582, Funder: Calcul Québec and Compute Canada, Funder: Compute Canada; funder-id: http://dx.doi.org/10.13039/100013020, Funder: Stiftung Universitätsmedizin Essen; funder-id: http://dx.doi.org/10.13039/501100010380, Funder: State of Saarland, Funder: Dr. Rolf M. Schwiete Foundation, Funder: Munich Clinician Scientist Programm, Funder: Netzwerk-Universitaetsmedizin-COVIM; Grant(s): NaFoUniMedCovid19, FKZ: 01KX2021, Funder: Federal Ministry of Education and Research, Funder: Leenaards Foundation, Funder: Santos-Suarez Foundation, Funder: Carigest, Funder: Istituto Buddista Italiano Soka Gakkai; Grant(s): 2020-2016_RIC_3 via project “PAT-COVID: Host genetics and pathogenetic mechanisms of COVID-19”, Funder: e-ASIA Joint Research Program (National Science and Technology Development Agency), 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.
- Published
- 2022