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 J.M. 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; 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:10.1371/journal.pgen.1010367

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 J.M. 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, 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^*

^*Corresponding author for this work

McGill University
Sir Mortimer B. Davis-Jewish General Hospital
Columbia University
Regeneron Pharmaceuticals, Inc.
Helix OpCo LLC
Children's Hospital of Philadelphia
University of Pennsylvania
University of Cambridge
University of Siena
Qatar Foundation HQ
University of Basel
University of Bonn
IMAGENE.ME SA
Wellcome Trust Sanger Institute
Medical University of Białystok
Institute of Molecular and Clinical Ophthalmology Basel
University of Southern California
Genentech Incorporated
Icahn School of Medicine at Mount Sinai
Vanda Pharmaceuticals Inc.
University of California at Los Angeles
Azienda Ospedaliera Universitaria Senese
University of Edinburgh
Royal Infirmary of Edinburgh
Genomics England
University of Santiago de Compostela
Instituto de Investigación Sanitaria de Santiago de Compostela
Centro de Investigacion Biomedica en Red Enfermedades Respiratorias (CIBERES)
Complejo Hospitalario Universitario de Santiago
University of Helsinki
Harvard University
Broad Institute
Massachusetts General Hospital
Kyoto University
Japan Society for the Promotion of Science
Uppsala University
Desert Research Institute
Renown Health
University of Tübingen
University of Cologne
King Abdulaziz Medical City - Riyadh
King Abdulaziz City for Science and Technology
King Saud bin Abdulaziz University for Health Sciences
King Faisal Specialist Hospital and Research Centre
Johns Hopkins University
University of Leicester
University of Lausanne
MNM Bioscience Inc.
Adam Mickiewicz University in Poznań
University of Medical Sciences Poznan
Chulalongkorn University
National Center for Global Health and Medicine
Institute of Science Tokyo
The University of Osaka
RIKEN
Keio University
Karolinska Institutet
The University of Tokyo
King's College London
Ludwig Maximilian University of Munich
Technical University of Munich
VA Medical Center
University of Montreal

Research output: Contribution to journal › Article › peer-review

43 Citations (Scopus)

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.

Original language	English
Article number	e1010367
Journal	PLoS Genetics
Volume	18
Issue number	11
DOIs	https://doi.org/10.1371/journal.pgen.1010367
Publication status	Published - 3 Nov 2022
Externally published	Yes

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10.1371/journal.pgen.1010367

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Butler-Laporte, G., Povysil, G., Kosmicki, J. A., Cirulli, E. T., Drivas, T., Furini, S., Saad, C., Schmidt, A., Olszewski, P., Korotko, U., Quinodoz, M., Çelik, E., Kundu, K., Walter, K., Jung, J., Stockwell, A. D., Sloofman, L. G., Jordan, D. M., Thompson, R. C., ... Brent Richards, J. (2022). Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative. PLoS Genetics, 18(11), Article e1010367. https://doi.org/10.1371/journal.pgen.1010367

@article{17137ee1dc864a79ababf617fce4e278,

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

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 = "Guillaume Butler-Laporte and Gundula Povysil and Kosmicki, \{Jack A.\} and Cirulli, \{Elizabeth T.\} and Theodore Drivas and Simone Furini and Chadi Saad and Axel Schmidt and Pawel Olszewski and Urszula Korotko and Mathieu Quinodoz and Elifnaz {\c C}elik and Kousik Kundu and Klaudia Walter and Junghyun Jung and Stockwell, \{Amy D.\} and Sloofman, \{Laura G.\} and Jordan, \{Daniel M.\} and Thompson, \{Ryan C.\} and \{Del Valle\}, Diane and Nicole Simons and Esther Cheng and Robert Sebra and Schadt, \{Eric E.\} and Seunghee Kim-Schulze and Sacha Gnjatic and Miriam Merad and Buxbaum, \{Joseph D.\} and Beckmann, \{Noam D.\} and Charney, \{Alexander W.\} and Bartlomiej Przychodzen and Timothy Chang and Pottinger, \{Tess D.\} and Ning Shang and Fabian Brand and Francesca Fava and Francesca Mari and Karolina Chwialkowska and Magdalena Niemira and Szymon Pula and \{Kenneth Baillie\}, J. and Alex Stuckey and Antonio Salas and Xabier Bello and Jacobo Pardo-Seco and Alberto G{\'o}mez-Carballa and Irene Rivero-Calle and Federico Martin{\'o}n-Torres and Andrea Ganna and Karczewski, \{Konrad J.\} and Kumar Veerapen and Mathieu Bourgey and Guillaume Bourque and Eveleigh, \{Robert J.M.\} and Vincenzo Forgetta and David Morrison and David Langlais and Mark Lathrop and Vincent Mooser and Tomoko Nakanishi and Robert Frithiof and Michael Hultstr{\"o}m and Miklos Lipcsey and Yanara Marincevic-Zuniga and Jessica Nordlund and \{Schiabor Barrett\}, \{Kelly M.\} and William Lee and Alexandre Bolze and Simon White and Stephen Riffle and Francisco Tanudjaja and Efren Sandoval and Iva Neveux and Shaun Dabe and Nicolas Casadei and Susanne Motameny and Manal Alaamery and Salam Massadeh and Nora Aljawini and Almutairi, \{Mansour S.\} and Arabi, \{Yaseen M.\} and Alqahtani, \{Saleh A.\} and \{Al Harthi\}, \{Fawz S.\} and Amal Almutairi and Fatima Alqubaishi and Sarah Alotaibi and Albandari Binowayn and Alsolm, \{Ebtehal A.\} and Bardisy, \{Hadeel El\} and Mohammad Fawzy and Fang Cai and Nicole Soranzo and Adam Butterworth and Center, \{Regeneron Genetics\} and Geschwind, \{Daniel H.\} and Stephanie Arteaga and Alexis Stephens and Butte, \{Manish J.\} and Boutros, \{Paul C.\} and Yamaguchi, \{Takafumi N.\} and Shu Tao and Stefan Eng and Timothy Sanders and Tung, \{Paul J.\} and Broudy, \{Michael E.\} and Yu Pan and Alfredo Gonzalez and Nikhil Chavan and Ruth Johnson and Bogdan Pasaniuc and Brian Yaspan and Sandra Smieszek and Carlo Rivolta and Stephanie Bibert and Bochud, \{Pierre Yves\} and Maciej Dabrowski and Pawel Zawadzki and Mateusz Sypniewski and El{\.z}bieta Kaja and Pajaree Chariyavilaskul and Voraphoj Nilaratanakul and Nattiya Hirankarn and Vorasuk Shotelersuk and Monnat Pongpanich and Chureerat Phokaew and Wanna Chetruengchai and Katsushi Tokunaga and Masaya Sugiyama and Yosuke Kawai and Takanori Hasegawa and Tatsuhiko Naito and Ho Namkoong and Ryuya Edahiro and Akinori Kimura and Seishi Ogawa and Takanori Kanai and Koichi Fukunaga and Yukinori Okada and Seiya Imoto and Satoru Miyano and Serghei Mangul and Abedalthagafi, \{Malak S.\} and Hugo Zeberg and Grzymski, \{Joseph J.\} and Washington, \{Nicole L.\} and Stephan Ossowski and Ludwig, \{Kerstin U.\} and Schulte, \{Eva C.\} and Olaf Riess and Marcin Moniuszko and Miroslaw Kwasniewski and Hamdi Mbarek and Ismail, \{Said I.\} and Anurag Verma and Goldstein, \{David B.\} and Krzysztof Kiryluk and Alessandra Renieri and Ferreira, \{Manuel A.R.\} and \{Brent Richards\}, J.",

note = "Publisher Copyright: Copyright: {\textcopyright} 2022 Butler-Laporte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2022",

month = nov,

day = "3",

doi = "10.1371/journal.pgen.1010367",

language = "English",

volume = "18",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "11",

}

Butler-Laporte, G, Povysil, G, Kosmicki, JA, Cirulli, ET, Drivas, T, Furini, S, Saad, C, Schmidt, A, Olszewski, P, Korotko, U, Quinodoz, M, Çelik, E, Kundu, K, Walter, K, Jung, J, Stockwell, AD, Sloofman, LG, Jordan, DM, Thompson, RC, Del Valle, D, Simons, N, Cheng, E, Sebra, R, Schadt, EE, Kim-Schulze, S, Gnjatic, S, Merad, M, Buxbaum, JD, Beckmann, ND, Charney, AW, Przychodzen, B, Chang, T, Pottinger, TD, Shang, N, Brand, F, Fava, F, Mari, F, Chwialkowska, K, Niemira, M, Pula, S, Kenneth Baillie, J, Stuckey, A, Salas, A, Bello, X, Pardo-Seco, J, Gómez-Carballa, A, Rivero-Calle, I, Martinón-Torres, F, Ganna, A, Karczewski, KJ, Veerapen, K, Bourgey, M, Bourque, G, Eveleigh, RJM, Forgetta, V, Morrison, D, Langlais, D, Lathrop, M, Mooser, V, Nakanishi, T, Frithiof, R, Hultström, M, Lipcsey, M, Marincevic-Zuniga, Y, Nordlund, J, Schiabor Barrett, KM, Lee, W, Bolze, A, White, S, Riffle, S, Tanudjaja, F, Sandoval, E, Neveux, I, Dabe, S, Casadei, N, Motameny, S, Alaamery, M, Massadeh, S, Aljawini, N, Almutairi, MS, Arabi, YM, Alqahtani, SA, Al Harthi, FS, Almutairi, A, Alqubaishi, F, Alotaibi, S, Binowayn, A, Alsolm, EA, Bardisy, HE, Fawzy, M, Cai, F, Soranzo, N, Butterworth, A, Center, RG, Geschwind, DH, Arteaga, S, Stephens, A, Butte, MJ, Boutros, PC, Yamaguchi, TN, Tao, S, Eng, S, Sanders, T, Tung, PJ, Broudy, ME, Pan, Y, Gonzalez, A, Chavan, N, Johnson, R, Pasaniuc, B, Yaspan, B, Smieszek, S, Rivolta, C, Bibert, S, Bochud, PY, Dabrowski, M, Zawadzki, P, Sypniewski, M, Kaja, E, Chariyavilaskul, P, Nilaratanakul, V, Hirankarn, N, Shotelersuk, V, Pongpanich, M, Phokaew, C, Chetruengchai, W, Tokunaga, K, Sugiyama, M, Kawai, Y, Hasegawa, T, Naito, T, Namkoong, H, Edahiro, R, Kimura, A, Ogawa, S, Kanai, T, Fukunaga, K, Okada, Y, Imoto, S, Miyano, S, Mangul, S, Abedalthagafi, MS, Zeberg, H, Grzymski, JJ, Washington, NL, Ossowski, S, Ludwig, KU, Schulte, EC, Riess, O, Moniuszko, M, Kwasniewski, M, Mbarek, H, Ismail, SI, Verma, A, Goldstein, DB, Kiryluk, K, Renieri, A, Ferreira, MAR & Brent Richards, J 2022, 'Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative', PLoS Genetics, vol. 18, no. 11, e1010367. https://doi.org/10.1371/journal.pgen.1010367

TY - JOUR

T1 - Exome-wide association study to identify rare variants influencing COVID-19 outcomes

T2 - Results from the Host Genetics Initiative

AU - Butler-Laporte, Guillaume

AU - Povysil, Gundula

AU - Kosmicki, Jack A.

AU - Cirulli, Elizabeth T.

AU - Drivas, Theodore

AU - Furini, Simone

AU - Saad, Chadi

AU - Schmidt, Axel

AU - Olszewski, Pawel

AU - Korotko, Urszula

AU - Quinodoz, Mathieu

AU - Çelik, Elifnaz

AU - Kundu, Kousik

AU - Walter, Klaudia

AU - Jung, Junghyun

AU - Stockwell, Amy D.

AU - Sloofman, Laura G.

AU - Jordan, Daniel M.

AU - Thompson, Ryan C.

AU - Del Valle, Diane

AU - Simons, Nicole

AU - Cheng, Esther

AU - Sebra, Robert

AU - Schadt, Eric E.

AU - Kim-Schulze, Seunghee

AU - Gnjatic, Sacha

AU - Merad, Miriam

AU - Buxbaum, Joseph D.

AU - Beckmann, Noam D.

AU - Charney, Alexander W.

AU - Przychodzen, Bartlomiej

AU - Chang, Timothy

AU - Pottinger, Tess D.

AU - Shang, Ning

AU - Brand, Fabian

AU - Fava, Francesca

AU - Mari, Francesca

AU - Chwialkowska, Karolina

AU - Niemira, Magdalena

AU - Pula, Szymon

AU - Kenneth Baillie, J.

AU - Stuckey, Alex

AU - Salas, Antonio

AU - Bello, Xabier

AU - Pardo-Seco, Jacobo

AU - Gómez-Carballa, Alberto

AU - Rivero-Calle, Irene

AU - Martinón-Torres, Federico

AU - Ganna, Andrea

AU - Karczewski, Konrad J.

AU - Veerapen, Kumar

AU - Bourgey, Mathieu

AU - Bourque, Guillaume

AU - Eveleigh, Robert J.M.

AU - Forgetta, Vincenzo

AU - Morrison, David

AU - Langlais, David

AU - Lathrop, Mark

AU - Mooser, Vincent

AU - Nakanishi, Tomoko

AU - Frithiof, Robert

AU - Hultström, Michael

AU - Lipcsey, Miklos

AU - Marincevic-Zuniga, Yanara

AU - Nordlund, Jessica

AU - Schiabor Barrett, Kelly M.

AU - Lee, William

AU - Bolze, Alexandre

AU - White, Simon

AU - Riffle, Stephen

AU - Tanudjaja, Francisco

AU - Sandoval, Efren

AU - Neveux, Iva

AU - Dabe, Shaun

AU - Casadei, Nicolas

AU - Motameny, Susanne

AU - Alaamery, Manal

AU - Massadeh, Salam

AU - Aljawini, Nora

AU - Almutairi, Mansour S.

AU - Arabi, Yaseen M.

AU - Alqahtani, Saleh A.

AU - Al Harthi, Fawz S.

AU - Almutairi, Amal

AU - Alqubaishi, Fatima

AU - Alotaibi, Sarah

AU - Binowayn, Albandari

AU - Alsolm, Ebtehal A.

AU - Bardisy, Hadeel El

AU - Fawzy, Mohammad

AU - Cai, Fang

AU - Soranzo, Nicole

AU - Butterworth, Adam

AU - Center, Regeneron Genetics

AU - Geschwind, Daniel H.

AU - Arteaga, Stephanie

AU - Stephens, Alexis

AU - Butte, Manish J.

AU - Boutros, Paul C.

AU - Yamaguchi, Takafumi N.

AU - Tao, Shu

AU - Eng, Stefan

AU - Sanders, Timothy

AU - Tung, Paul J.

AU - Broudy, Michael E.

AU - Pan, Yu

AU - Gonzalez, Alfredo

AU - Chavan, Nikhil

AU - Johnson, Ruth

AU - Pasaniuc, Bogdan

AU - Yaspan, Brian

AU - Smieszek, Sandra

AU - Rivolta, Carlo

AU - Bibert, Stephanie

AU - Bochud, Pierre Yves

AU - Dabrowski, Maciej

AU - Zawadzki, Pawel

AU - Sypniewski, Mateusz

AU - Kaja, Elżbieta

AU - Chariyavilaskul, Pajaree

AU - Nilaratanakul, Voraphoj

AU - Hirankarn, Nattiya

AU - Shotelersuk, Vorasuk

AU - Pongpanich, Monnat

AU - Phokaew, Chureerat

AU - Chetruengchai, Wanna

AU - Tokunaga, Katsushi

AU - Sugiyama, Masaya

AU - Kawai, Yosuke

AU - Hasegawa, Takanori

AU - Naito, Tatsuhiko

AU - Namkoong, Ho

AU - Edahiro, Ryuya

AU - Kimura, Akinori

AU - Ogawa, Seishi

AU - Kanai, Takanori

AU - Fukunaga, Koichi

AU - Okada, Yukinori

AU - Imoto, Seiya

AU - Miyano, Satoru

AU - Mangul, Serghei

AU - Abedalthagafi, Malak S.

AU - Zeberg, Hugo

AU - Grzymski, Joseph J.

AU - Washington, Nicole L.

AU - Ossowski, Stephan

AU - Ludwig, Kerstin U.

AU - Schulte, Eva C.

AU - Riess, Olaf

AU - Moniuszko, Marcin

AU - Kwasniewski, Miroslaw

AU - Mbarek, Hamdi

AU - Ismail, Said I.

AU - Verma, Anurag

AU - Goldstein, David B.

AU - Kiryluk, Krzysztof

AU - Renieri, Alessandra

AU - Ferreira, Manuel A.R.

AU - Brent Richards, J.

N1 - Publisher Copyright: Copyright: © 2022 Butler-Laporte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2022/11/3

Y1 - 2022/11/3

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85141890269

U2 - 10.1371/journal.pgen.1010367

DO - 10.1371/journal.pgen.1010367

M3 - Article

C2 - 36327219

AN - SCOPUS:85141890269

SN - 1553-7390

VL - 18

JO - PLoS Genetics

JF - PLoS Genetics

IS - 11

M1 - e1010367

ER -

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

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