PLoS Genetics (Nov 2022)

Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.

  • 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

DOI
https://doi.org/10.1371/journal.pgen.1010367
Journal volume & issue
Vol. 18, no. 11
p. e1010367

Abstract

Read online

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.