학술논문
Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.
Document Type
article
Author
Guillaume Butler-Laporte; Gundula Povysil; Jack A Kosmicki; Elizabeth T Cirulli; Theodore Drivas; Simone Furini; Chadi Saad; Axel Schmidt; Pawel Olszewski; Urszula Korotko; Mathieu Quinodoz; Elifnaz Çelik; Kousik Kundu; Klaudia Walter; Junghyun Jung; Amy D Stockwell; Laura G Sloofman; Daniel M Jordan; Ryan C Thompson; Diane Del Valle; Nicole Simons; Esther Cheng; Robert Sebra; Eric E Schadt; Seunghee Kim-Schulze; Sacha Gnjatic; Miriam Merad; Joseph D Buxbaum; Noam D Beckmann; Alexander W Charney; Bartlomiej Przychodzen; Timothy Chang; Tess D Pottinger; Ning Shang; Fabian Brand; Francesca Fava; Francesca Mari; Karolina Chwialkowska; Magdalena Niemira; Szymon Pula; J Kenneth Baillie; Alex Stuckey; Antonio Salas; Xabier Bello; Jacobo Pardo-Seco; Alberto Gómez-Carballa; Irene Rivero-Calle; Federico Martinón-Torres; Andrea Ganna; Konrad J Karczewski; Kumar Veerapen; Mathieu Bourgey; Guillaume Bourque; Robert Jm Eveleigh; Vincenzo Forgetta; David Morrison; David Langlais; Mark Lathrop; Vincent Mooser; Tomoko Nakanishi; Robert Frithiof; Michael Hultström; Miklos Lipcsey; Yanara Marincevic-Zuniga; Jessica Nordlund; Kelly M Schiabor Barrett; William Lee; Alexandre Bolze; Simon White; Stephen Riffle; Francisco Tanudjaja; Efren Sandoval; Iva Neveux; Shaun Dabe; Nicolas Casadei; Susanne Motameny; Manal Alaamery; Salam Massadeh; Nora Aljawini; Mansour S Almutairi; Yaseen M Arabi; Saleh A Alqahtani; Fawz S Al Harthi; Amal Almutairi; Fatima Alqubaishi; Sarah Alotaibi; Albandari Binowayn; Ebtehal A Alsolm; Hadeel El Bardisy; Mohammad Fawzy; Fang Cai; Nicole Soranzo; Adam Butterworth; 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; Daniel H Geschwind; Stephanie Arteaga; Alexis Stephens; Manish J Butte; Paul C Boutros; Takafumi N Yamaguchi; Shu Tao; Stefan Eng; Timothy Sanders; Paul J Tung; Michael E Broudy; Yu Pan; Alfredo Gonzalez; Nikhil Chavan; Ruth Johnson; Bogdan Pasaniuc; Brian Yaspan; Sandra Smieszek; Carlo Rivolta; Stephanie Bibert; Pierre-Yves Bochud; Maciej Dabrowski; Pawel Zawadzki; Mateusz Sypniewski; Elżbieta Kaja; Pajaree Chariyavilaskul; Voraphoj Nilaratanakul; Nattiya Hirankarn; Vorasuk Shotelersuk; Monnat Pongpanich; Chureerat Phokaew; Wanna Chetruengchai; Katsushi Tokunaga; Masaya Sugiyama; Yosuke Kawai; Takanori Hasegawa; Tatsuhiko Naito; Ho Namkoong; Ryuya Edahiro; Akinori Kimura; Seishi Ogawa; Takanori Kanai; Koichi Fukunaga; Yukinori Okada; Seiya Imoto; Satoru Miyano; Serghei Mangul; Malak S Abedalthagafi; Hugo Zeberg; Joseph J Grzymski; Nicole L Washington; Stephan Ossowski; Kerstin U Ludwig; Eva C Schulte; Olaf Riess; Marcin Moniuszko; Miroslaw Kwasniewski; Hamdi Mbarek; Said I Ismail; Anurag Verma; David B Goldstein; Krzysztof Kiryluk; Alessandra Renieri; Manuel A R Ferreira; J Brent Richards
Source
PLoS Genetics, Vol 18, Iss 11, p e1010367 (2022)
Subject
Language
English
ISSN
1553-7390
1553-7404
1553-7404
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.