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[Preprint]. 2021 Feb 27:2020.10.28.20221804.

doi: 10.1101/2020.10.28.20221804.

A catalog of associations between rare coding variants and COVID-19 outcomes

J A Kosmicki¹, J E Horowitz¹, N Banerjee¹, R Lanche¹, A Marcketta¹, E Maxwell¹, X Bai¹, D Sun¹, J D Backman¹, D Sharma¹, H M Kang¹, C O'Dushlaine¹, A Yadav¹, A J Mansfield¹, A H Li¹, K Watanabe¹, L Gurski¹, S E McCarthy¹, A E Locke¹, S Khalid¹, S O'Keeffe¹, J Mbatchou¹, O Chazara², Y Huang², E Kvikstad³, A O'Neill², P Nioi², M M Parker⁴, S Petrovski², H Runz⁵, J D Szustakowski², Q Wang², E Wong⁵, A Cordova-Palomera⁶, E N Smith⁶, S Szalma⁶, X Zheng⁷, S Esmaeeli⁷, J W Davis⁷, Y-P Lai⁸, X Chen⁸, A E Justice⁹, J B Leader⁹, T Mirshahi⁹, D J Carey⁹, A Verma¹⁰, G Sirugo¹⁰, M D Ritchie¹⁰, D J Rader¹⁰, G Povysil¹¹, D B Goldstein^{11

12}, K Kiryluk^{11

13}, E Pairo-Castineira^{14

15}, K Rawlik¹⁴, D Pasko¹⁶, S Walker¹⁶, A Meynert¹⁵, A Kousathanas¹⁶, L Moutsianas¹⁶, A Tenesa^{14

15

17}, M Caulfield^{16

18}, R Scott^{16

19}, J F Wilson^{15

17}, J K Baillie^{14

15

20}, G Butler-Laporte^{21

22}, T Nakanishi^{21

23

24

25}, M Lathrop^{23

26}, J B Richards^{21

22

23

27}; Regeneron Genetics Center; UKB Exome Sequencing Consortium; M Jones¹, S Balasubramanian¹, W Salerno¹, A R Shuldiner¹, J Marchini¹, J D Overton¹, L Habegger¹, M N Cantor¹, J G Reid¹, A Baras¹, G R Abecasis¹, M A Ferreira¹

Affiliations

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

PMID: 33655273
PMCID: PMC7924298
DOI: 10.1101/2020.10.28.20221804

A catalog of associations between rare coding variants and COVID-19 outcomes

J A Kosmicki et al. medRxiv. 2021.

[Preprint]. 2021 Feb 27:2020.10.28.20221804.

doi: 10.1101/2020.10.28.20221804.

Authors

Affiliations

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

PMID: 33655273
PMCID: PMC7924298
DOI: 10.1101/2020.10.28.20221804

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 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 (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 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, with results publicly browsable at https://rgc-covid19.regeneron.com.

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Conflict of interest statement

Competing interests J.E.H., J.A.K., A.D., D.S., N.B, A.Y., A.M., R.L., E.M., X.B., D.S., F.S.P.K., J.D.B., C.O’D., A.J.M., D.A.T., A.H.L., J.M., K.W., L.G., S.E.M, H.M.K., L.D., E.S., M.J., S.B., K.S.M, W.J.S., A.R.S., A.E.L., J.M., J.O., L.H., M.N.C., J.G.R., A.B., G.R.A., and M.A.F. are current employees and/or stockholders of Regeneron Genetics Center or Regeneron Pharmaceuticals. X.Z., S.E., J.W.D. are employees of AbbVie and may hold stock in AbbVie. Financial support for this research was provided by AbbVie through the UKB Exome Sequencing Consortium. AbbVie participated in the interpretation of data, review, and approval of the publication. P.N. and M.M.P are employees and stockholders of Alnylam Pharmaceuticals. J.B.R. has served as an advisor to GlaxoSmithKline and Deerfield Capital and these agencies had no role in the design, implementation or interpretation of this study. S.S., E.W., A.C.P., and E.N.S. are employed by Takeda. S.S. holds shares in Takeda and Janssen. The other authors declare no competing interests.

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This is a preprint.

A catalog of associations between rare coding variants and COVID-19 outcomes

Affiliations

A catalog of associations between rare coding variants and COVID-19 outcomes

Authors

Affiliations

Abstract

Conflict of interest statement

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