Butler-Laporte, Guillaume, Povysil, Gundula ORCID: 0000-0003-4625-5909, Kosmicki, Jack A., Cirulli, Elizabeth T., Drivas, Theodore ORCID: 0000-0002-8717-0111, Furini, Simone ORCID: 0000-0002-1099-8279, Saad, Chadi, Schmidt, Axel, Olszewski, Pawel, Korotko, Urszula ORCID: 0000-0002-1779-8368, Quinodoz, Mathieu, Celik, 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 ORCID: 0000-0003-1992-1654, Chwialkowska, Karolina, Niemira, Magdalena ORCID: 0000-0002-0701-4961, Pula, Szymon, Baillie, J. Kenneth, Stuckey, Alex, Salas, Antonio ORCID: 0000-0002-2336-702X, Bello, Xabier, Pardo-Seco, Jacobo, Gomez-Carballa, Alberto, Rivero-Calle, Irene, Martinon-Torres, Federico ORCID: 0000-0002-9023-581X, Ganna, Andrea ORCID: 0000-0002-8147-240X, Karczewski, Konrad J., Veerapen, Kumar, Bourgey, Mathieu ORCID: 0000-0002-8432-834X, Bourque, Guillaume ORCID: 0000-0002-3933-9656, Eveleigh, Robert Jm, Forgetta, Vincenzo, Morrison, David, Langlais, David ORCID: 0000-0003-4429-0110, Lathrop, Mark, Mooser, Vincent, Nakanishi, Tomoko, Frithiof, Robert, Hultstrom, Michael, Lipcsey, Miklos, Marincevic-Zuniga, Yanara, Nordlund, Jessica, Barrett, Kelly M. Schiabor, Lee, William, Bolze, Alexandre, White, Simon, Riffle, Stephen, Tanudjaja, Francisco, Sandoval, Efren, Neveux, Iva, Dabe, Shaun, Casadei, Nicolas ORCID: 0000-0003-2209-0580, 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 ORCID: 0000-0002-5245-6507, 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 ORCID: 0000-0003-4150-3985, Zawadzki, Pawel, Sypniewski, Mateusz ORCID: 0000-0002-0108-0255, Kaja, Elzbieta ORCID: 0000-0003-1277-6140, Chariyavilaskul, Pajaree, Nilaratanakul, Voraphoj, Hirankarn, Nattiya, Shotelersuk, Vorasuk, Pongpanich, Monnat, Phokaew, Chureerat ORCID: 0000-0002-4246-2604, 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 ORCID: 0000-0001-7118-1249, Grzymski, Joseph J., Washington, Nicole L., Ossowski, Stephan ORCID: 0000-0002-7416-9568, 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. and Richards, J. Brent (2022). Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative. PLoS Genet., 18 (11). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7404

Full text not available from this repository.

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. 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Butler-Laporte, GuillaumeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Povysil, GundulaUNSPECIFIEDorcid.org/0000-0003-4625-5909UNSPECIFIED
Kosmicki, Jack A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cirulli, Elizabeth T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Drivas, TheodoreUNSPECIFIEDorcid.org/0000-0002-8717-0111UNSPECIFIED
Furini, SimoneUNSPECIFIEDorcid.org/0000-0002-1099-8279UNSPECIFIED
Saad, ChadiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, AxelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olszewski, PawelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korotko, UrszulaUNSPECIFIEDorcid.org/0000-0002-1779-8368UNSPECIFIED
Quinodoz, MathieuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Celik, ElifnazUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kundu, KousikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walter, KlaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jung, JunghyunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stockwell, Amy D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sloofman, Laura G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jordan, Daniel M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thompson, Ryan C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Del Valle, DianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simons, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cheng, EstherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sebra, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schadt, Eric E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim-Schulze, SeungheeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gnjatic, SachaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merad, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buxbaum, Joseph D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beckmann, Noam D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Charney, Alexander W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Przychodzen, BartlomiejUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chang, TimothyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pottinger, Tess D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shang, NingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brand, FabianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fava, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mari, FrancescaUNSPECIFIEDorcid.org/0000-0003-1992-1654UNSPECIFIED
Chwialkowska, KarolinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niemira, MagdalenaUNSPECIFIEDorcid.org/0000-0002-0701-4961UNSPECIFIED
Pula, SzymonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baillie, J. KennethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stuckey, AlexUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Salas, AntonioUNSPECIFIEDorcid.org/0000-0002-2336-702XUNSPECIFIED
Bello, XabierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pardo-Seco, JacoboUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gomez-Carballa, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rivero-Calle, IreneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martinon-Torres, FedericoUNSPECIFIEDorcid.org/0000-0002-9023-581XUNSPECIFIED
Ganna, AndreaUNSPECIFIEDorcid.org/0000-0002-8147-240XUNSPECIFIED
Karczewski, Konrad J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Veerapen, KumarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bourgey, MathieuUNSPECIFIEDorcid.org/0000-0002-8432-834XUNSPECIFIED
Bourque, GuillaumeUNSPECIFIEDorcid.org/0000-0002-3933-9656UNSPECIFIED
Eveleigh, Robert JmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Forgetta, VincenzoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morrison, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langlais, DavidUNSPECIFIEDorcid.org/0000-0003-4429-0110UNSPECIFIED
Lathrop, MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mooser, VincentUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nakanishi, TomokoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frithiof, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hultstrom, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lipcsey, MiklosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marincevic-Zuniga, YanaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nordlund, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barrett, Kelly M. SchiaborUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, WilliamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bolze, AlexandreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
White, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riffle, StephenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tanudjaja, FranciscoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sandoval, EfrenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neveux, IvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dabe, ShaunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Casadei, NicolasUNSPECIFIEDorcid.org/0000-0003-2209-0580UNSPECIFIED
Motameny, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alaamery, ManalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Massadeh, SalamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aljawini, NoraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Almutairi, Mansour S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arabi, Yaseen M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alqahtani, Saleh A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al Harthi, Fawz S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Almutairi, AmalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alqubaishi, FatimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alotaibi, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Binowayn, AlbandariUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alsolm, Ebtehal A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
El Bardisy, HadeelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fawzy, MohammadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cai, FangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soranzo, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Butterworth, AdamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geschwind, Daniel H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arteaga, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stephens, AlexisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Butte, Manish J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boutros, Paul C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yamaguchi, Takafumi N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tao, ShuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eng, StefanUNSPECIFIEDorcid.org/0000-0002-5245-6507UNSPECIFIED
Sanders, TimothyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tung, Paul J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Broudy, Michael E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pan, YuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez, AlfredoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chavan, NikhilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johnson, RuthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasaniuc, BogdanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yaspan, BrianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smieszek, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rivolta, CarloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bibert, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bochud, Pierre-YvesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dabrowski, MaciejUNSPECIFIEDorcid.org/0000-0003-4150-3985UNSPECIFIED
Zawadzki, PawelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sypniewski, MateuszUNSPECIFIEDorcid.org/0000-0002-0108-0255UNSPECIFIED
Kaja, ElzbietaUNSPECIFIEDorcid.org/0000-0003-1277-6140UNSPECIFIED
Chariyavilaskul, PajareeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nilaratanakul, VoraphojUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hirankarn, NattiyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shotelersuk, VorasukUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pongpanich, MonnatUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Phokaew, ChureeratUNSPECIFIEDorcid.org/0000-0002-4246-2604UNSPECIFIED
Chetruengchai, WannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tokunaga, KatsushiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sugiyama, MasayaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kawai, YosukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hasegawa, TakanoriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Naito, TatsuhikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Namkoong, HoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Edahiro, RyuyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kimura, AkinoriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ogawa, SeishiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kanai, TakanoriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fukunaga, KoichiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Okada, YukinoriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Imoto, SeiyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miyano, SatoruUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mangul, SergheiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abedalthagafi, Malak S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zeberg, HugoUNSPECIFIEDorcid.org/0000-0001-7118-1249UNSPECIFIED
Grzymski, Joseph J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Washington, Nicole L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ossowski, StephanUNSPECIFIEDorcid.org/0000-0002-7416-9568UNSPECIFIED
Ludwig, Kerstin U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulte, Eva C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riess, OlafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moniuszko, MarcinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kwasniewski, MiroslawUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mbarek, HamdiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ismail, Said I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Verma, AnuragUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldstein, David B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kiryluk, KrzysztofUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Renieri, AlessandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferreira, Manuel A. R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richards, J. BrentUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-699392
DOI: 10.1371/journal.pgen.1010367
Journal or Publication Title: PLoS Genet.
Volume: 18
Number: 11
Date: 2022
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1553-7404
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROTEINSMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69939

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