Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
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Published:2022-11-03
Issue:11
Volume:18
Page:e1010367
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ISSN:1553-7404
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Container-title:PLOS Genetics
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language:en
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Short-container-title:PLoS Genet
Author:
Butler-Laporte GuillaumeORCID, Povysil GundulaORCID, Kosmicki Jack A.ORCID, Cirulli Elizabeth T.ORCID, Drivas TheodoreORCID, Furini Simone, Saad ChadiORCID, Schmidt Axel, Olszewski PawelORCID, Korotko UrszulaORCID, Quinodoz MathieuORCID, Çelik ElifnazORCID, Kundu KousikORCID, Walter KlaudiaORCID, Jung Junghyun, Stockwell Amy D., Sloofman Laura G.ORCID, Jordan Daniel M.ORCID, Thompson Ryan C.ORCID, Del Valle DianeORCID, Simons NicoleORCID, 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 TimothyORCID, Pottinger Tess D., Shang Ning, Brand FabianORCID, Fava Francesca, Mari Francesca, Chwialkowska KarolinaORCID, Niemira MagdalenaORCID, Pula SzymonORCID, Baillie J Kenneth, Stuckey AlexORCID, Salas Antonio, Bello XabierORCID, Pardo-Seco Jacobo, Gómez-Carballa Alberto, Rivero-Calle Irene, Martinón-Torres Federico, Ganna Andrea, Karczewski Konrad J.ORCID, Veerapen Kumar, Bourgey MathieuORCID, Bourque GuillaumeORCID, Eveleigh Robert JMORCID, Forgetta Vincenzo, Morrison DavidORCID, Langlais DavidORCID, Lathrop Mark, Mooser VincentORCID, Nakanishi TomokoORCID, Frithiof RobertORCID, Hultström MichaelORCID, Lipcsey MiklosORCID, Marincevic-Zuniga Yanara, Nordlund JessicaORCID, Schiabor Barrett Kelly M.ORCID, Lee William, Bolze AlexandreORCID, White SimonORCID, Riffle Stephen, Tanudjaja Francisco, Sandoval Efren, Neveux Iva, Dabe ShaunORCID, Casadei NicolasORCID, Motameny SusanneORCID, Alaamery Manal, Massadeh SalamORCID, Aljawini Nora, Almutairi Mansour S.ORCID, Arabi Yaseen M.ORCID, Alqahtani Saleh A., Al Harthi Fawz S., Almutairi Amal, Alqubaishi Fatima, Alotaibi Sarah, Binowayn Albandari, Alsolm Ebtehal A., El Bardisy Hadeel, Fawzy MohammadORCID, Cai Fang, Soranzo Nicole, Butterworth Adam, Geschwind Daniel H., Arteaga StephanieORCID, Stephens AlexisORCID, Butte Manish J., Boutros Paul C., Yamaguchi Takafumi N.ORCID, Tao Shu, Eng StefanORCID, Sanders Timothy, Tung Paul J., Broudy Michael E., Pan Yu, Gonzalez AlfredoORCID, Chavan Nikhil, Johnson RuthORCID, Pasaniuc Bogdan, Yaspan BrianORCID, Smieszek SandraORCID, Rivolta CarloORCID, Bibert Stephanie, Bochud Pierre-YvesORCID, Dabrowski MaciejORCID, Zawadzki PawelORCID, Sypniewski Mateusz, Kaja ElżbietaORCID, Chariyavilaskul PajareeORCID, Nilaratanakul VoraphojORCID, Hirankarn NattiyaORCID, Shotelersuk VorasukORCID, Pongpanich MonnatORCID, Phokaew ChureeratORCID, Chetruengchai WannaORCID, Tokunaga Katsushi, Sugiyama MasayaORCID, Kawai YosukeORCID, Hasegawa TakanoriORCID, Naito Tatsuhiko, Namkoong HoORCID, Edahiro Ryuya, Kimura Akinori, Ogawa Seishi, Kanai Takanori, Fukunaga Koichi, Okada Yukinori, Imoto Seiya, Miyano SatoruORCID, Mangul SergheiORCID, Abedalthagafi Malak S., Zeberg HugoORCID, Grzymski Joseph J.ORCID, Washington Nicole L., Ossowski StephanORCID, Ludwig Kerstin U.ORCID, Schulte Eva C.ORCID, Riess Olaf, Moniuszko Marcin, Kwasniewski Miroslaw, Mbarek Hamdi, Ismail Said I., Verma AnuragORCID, Goldstein David B.ORCID, Kiryluk KrzysztofORCID, Renieri AlessandraORCID, Ferreira Manuel A. R., Richards J BrentORCID, , , , , , , ,
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.
Publisher
Public Library of Science (PLoS)
Subject
Cancer Research,Genetics (clinical),Genetics,Molecular Biology,Ecology, Evolution, Behavior and Systematics
Cited by
21 articles.
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