Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals

Jack A Kosmicki; Julie E Horowitz; Nilanjana Banerjee; Rouel Lanche; Anthony Marcketta; Evan Maxwell; Xiaodong Bai; Dylan Sun; Joshua D Backman; Deepika Sharma; Fabricio S P Kury; Hyun M Kang; Colm O'Dushlaine; Ashish Yadav; Adam J Mansfield; Alexander H Li; Kyoko Watanabe; Lauren Gurski; Shane E McCarthy; Adam E Locke; Shareef Khalid; Sean O'Keeffe; Joelle Mbatchou; Olympe Chazara; Yunfeng Huang; Erika Kvikstad; Amanda O'Neill; Paul Nioi; Meg M Parker; Slavé Petrovski; Heiko Runz; Joseph D Szustakowski; Quanli Wang; Emily Wong; Aldo Cordova-Palomera; Erin N Smith; Sandor Szalma; Xiuwen Zheng; Sahar Esmaeeli; Justin W Davis; Yi-Pin Lai; Xing Chen; Anne E Justice; Joseph B Leader; Tooraj Mirshahi; David J Carey; Anurag Verma; Giorgio Sirugo; Marylyn D Ritchie; Daniel J Rader; Gundula Povysil; David B Goldstein; Krzysztof Kiryluk; Erola Pairo-Castineira; Konrad Rawlik; Dorota Pasko; Susan Walker; Alison Meynert; Athanasios Kousathanas; Loukas Moutsianas; Albert Tenesa; Mark Caulfield; Richard Scott; James F Wilson; J Kenneth Baillie; Guillaume Butler-Laporte; Tomoko Nakanishi; Mark Lathrop; J Brent Richards; Regeneron Genetics Center; UKB Exome Sequencing Consortium; Marcus Jones; Suganthi Balasubramanian; William Salerno; Alan R Shuldiner; Jonathan Marchini; John D Overton; Lukas Habegger; Michael N Cantor; Jeffrey G Reid; Aris Baras; Goncalo R Abecasis; Manuel A R Ferreira

doi:10.1016/j.ajhg.2021.05.017

Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals

Am J Hum Genet. 2021 Jul 1;108(7):1350-1355. doi: 10.1016/j.ajhg.2021.05.017. Epub 2021 Jun 3.

Authors

Jack A Kosmicki¹, Julie E Horowitz¹, Nilanjana Banerjee¹, Rouel Lanche¹, Anthony Marcketta¹, Evan Maxwell¹, Xiaodong Bai¹, Dylan Sun¹, Joshua D Backman¹, Deepika Sharma¹, Fabricio S P Kury¹, Hyun M Kang¹, Colm O'Dushlaine¹, Ashish Yadav¹, Adam J Mansfield¹, Alexander H Li¹, Kyoko Watanabe¹, Lauren Gurski¹, Shane E McCarthy¹, Adam E Locke¹, Shareef Khalid¹, Sean O'Keeffe¹, Joelle Mbatchou¹, Olympe Chazara², Yunfeng Huang³, Erika Kvikstad⁴, Amanda O'Neill², Paul Nioi⁵, Meg M Parker⁵, Slavé Petrovski², Heiko Runz³, Joseph D Szustakowski⁴, Quanli Wang², Emily Wong⁶, Aldo Cordova-Palomera⁶, Erin N Smith⁶, Sandor Szalma⁶, Xiuwen Zheng⁷, Sahar Esmaeeli⁷, Justin W Davis⁷, Yi-Pin Lai⁸, Xing Chen⁸, Anne E Justice⁹, Joseph B Leader⁹, Tooraj Mirshahi⁹, David J Carey⁹, Anurag Verma¹⁰, Giorgio Sirugo¹⁰, Marylyn D Ritchie¹⁰, Daniel J Rader¹⁰, Gundula Povysil¹¹, David B Goldstein¹², Krzysztof Kiryluk¹³, Erola Pairo-Castineira¹⁴, Konrad Rawlik¹⁵, Dorota Pasko¹⁶, Susan Walker¹⁶, Alison Meynert¹⁷, Athanasios Kousathanas¹⁶, Loukas Moutsianas¹⁶, Albert Tenesa¹⁸, Mark Caulfield¹⁹, Richard Scott²⁰, James F Wilson²¹, J Kenneth Baillie²², Guillaume Butler-Laporte²³, Tomoko Nakanishi²⁴, Mark Lathrop²⁵, J Brent Richards²⁶; Regeneron Genetics Center; UKB Exome Sequencing Consortium; Marcus Jones¹, Suganthi Balasubramanian¹, William Salerno¹, Alan R Shuldiner¹, Jonathan Marchini¹, John D Overton¹, Lukas Habegger¹, Michael N Cantor¹, Jeffrey G Reid¹, Aris Baras¹, Goncalo R Abecasis²⁷, Manuel A R Ferreira²⁸

Affiliations

¹ Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
² Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB2 0AA, UK.
³ Biogen, 300 Binney Street, Cambridge, MA 02142, USA.
⁴ Bristol Myers Squibb, Route 206 and Province Line Road, Princeton, NJ 08543, USA.
⁵ Alnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
⁶ Takeda California, Inc., 9625 Towne Centre Drive, San Diego, CA 92121, USA.
⁷ AbbVie, Inc., 1 N. Waukegan Road, North Chicago, IL 60064, USA.
⁸ Pfizer, Inc., 1 Portland Street, Cambridge, MA 02139, USA.
⁹ Geisinger, Danville, PA 17822, USA.
¹⁰ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹¹ Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
¹² Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
¹³ Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Division of Nephrology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
¹⁴ Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
¹⁵ Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK.
¹⁶ Genomics England, London EC1M 6BQ, UK.
¹⁷ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
¹⁸ Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK; Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Teviot Place, Edinburgh EH8 9AG, UK.
¹⁹ Genomics England, London EC1M 6BQ, UK; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
²⁰ Genomics England, London EC1M 6BQ, UK; Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
²¹ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK; Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Teviot Place, Edinburgh EH8 9AG, UK.
²² Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK; Intensive Care Unit, Royal Infirmary of Edinburgh, 54 Little France Drive, Edinburgh EH16 5SA, UK.
²³ Lady Davis Institute, Jewish General Hospital, Montréal, QC H3T 1E2, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, QC H3A 0G4, Canada.
²⁴ Lady Davis Institute, Jewish General Hospital, Montréal, QC H3T 1E2, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada; Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
²⁵ Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada; Canadian Centre for Computational Genomics, McGill University, Montréal, QC H3A 0G4, Canada.
²⁶ Lady Davis Institute, Jewish General Hospital, Montréal, QC H3T 1E2, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, QC H3A 0G4, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada; Department of Twins Research, King's College London, London WC2R 2LS, UK.
²⁷ Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. Electronic address: [email protected].
²⁸ Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. Electronic address: [email protected].

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, and results are publicly available through the Regeneron Genetics Center COVID-19 Results Browser.

Keywords: COVID-19; SARS-CoV-2; TLR7; ZC3HAV1; association; burden; exome sequencing; genetics; rare variants.

MeSH terms

COVID-19 / diagnosis*
COVID-19 / genetics*
COVID-19 / immunology
COVID-19 / therapy
Exome / genetics*
Exome Sequencing*
Female
Genetic Predisposition to Disease*
Hospitalization / statistics & numerical data*
Humans
Interferons / genetics
Male
Prognosis
SARS-CoV-2
Sample Size

Substances

Interferons

Abstract

MeSH terms

Substances

Grants and funding