. 2021 Apr;27(4):659-667.

doi: 10.1038/s41591-021-01281-1. Epub 2021 Feb 25.

A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity

Sirui Zhou^#^{1

2}, Guillaume Butler-Laporte^#^{1

2}, Tomoko Nakanishi^#^{1

3

4

5}, David R Morrison¹, Jonathan Afilalo^{1

2

6}, Marc Afilalo^{1

7}, Laetitia Laurent¹, Maik Pietzner⁸, Nicola Kerrison⁸, Kaiqiong Zhao^{1

2}, Elsa Brunet-Ratnasingham^{9

10}, Danielle Henry¹, Nofar Kimchi¹, Zaman Afrasiabi¹, Nardin Rezk¹, Meriem Bouab¹, Louis Petitjean¹, Charlotte Guzman¹, Xiaoqing Xue¹, Chris Tselios¹, Branka Vulesevic¹, Olumide Adeleye¹, Tala Abdullah¹, Noor Almamlouk¹, Yiheng Chen^{1

3}, Michaël Chassé⁹, Madeleine Durand⁹, Clare Paterson¹¹, Johan Normark¹², Robert Frithiof¹³, Miklós Lipcsey^{13

14}, Michael Hultström^{13

15}, Celia M T Greenwood^{1

2

16}, Hugo Zeberg¹⁷, Claudia Langenberg^{8

18}, Elin Thysell¹⁹, Michael Pollak^{1

20}, Vincent Mooser³, Vincenzo Forgetta¹, Daniel E Kaufmann^{9

21}, J Brent Richards^{22

23

24

25}

Affiliations

¹ Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Quebec, Canada.
² Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Quebec, Canada.
³ Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
⁴ Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁵ Research Fellow, Japan Society for the Promotion of Science, Tokyo, Japan.
⁶ Department of Medicine, Division of Cardiology, McGill University, Montréal, Quebec, Canada.
⁷ Department of Emergency Medicine, Jewish General Hospital, McGill University, Montréal, Quebec, Canada.
⁸ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
⁹ Research Centre of the Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada.
¹⁰ Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, Quebec, Canada.
¹¹ SomaLogic, Inc., Boulder, CO, USA.
¹² Molecular Infection Medicine Sweden (MIMS) and Wallenberg Center for Molecular Medicine, Department of Clinical Microbiology, Section of Infection and Immunology, Umeå University, Umeå, Sweden.
¹³ Anaesthesiology and Intensive Care Medicine, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹⁴ Hedenstierna Laboratory, CIRRUS, Anaesthesiology and Intensive Care Medicine, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹⁵ Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
¹⁶ Gerald Bronfman Department of Oncology, McGill University, Montréal, Quebec, Canada.
¹⁷ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
¹⁸ Computational Medicine, Berlin Institute of Health, Charité University Medicine Berlin, Berlin, Germany.
¹⁹ Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
²⁰ Departments of Medicine and Oncology, McGill University, Montréal, Quebec, Canada.
²¹ Department of Medicine, Université de Montréal, Montréal, Quebec, Canada.
²² Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Quebec, Canada. brent.richards@mcgill.ca.
²³ Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Quebec, Canada. brent.richards@mcgill.ca.
²⁴ Department of Human Genetics, McGill University, Montréal, Quebec, Canada. brent.richards@mcgill.ca.
²⁵ Department of Twin Research, King's College London, London, UK. brent.richards@mcgill.ca.

^# Contributed equally.

PMID: 33633408
DOI: 10.1038/s41591-021-01281-1

A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity

Sirui Zhou et al. Nat Med. 2021 Apr.

. 2021 Apr;27(4):659-667.

doi: 10.1038/s41591-021-01281-1. Epub 2021 Feb 25.

Authors

Affiliations

¹ Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Quebec, Canada.
² Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Quebec, Canada.
³ Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
⁴ Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁵ Research Fellow, Japan Society for the Promotion of Science, Tokyo, Japan.
⁶ Department of Medicine, Division of Cardiology, McGill University, Montréal, Quebec, Canada.
⁷ Department of Emergency Medicine, Jewish General Hospital, McGill University, Montréal, Quebec, Canada.
⁸ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
⁹ Research Centre of the Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada.
¹⁰ Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, Quebec, Canada.
¹¹ SomaLogic, Inc., Boulder, CO, USA.
¹² Molecular Infection Medicine Sweden (MIMS) and Wallenberg Center for Molecular Medicine, Department of Clinical Microbiology, Section of Infection and Immunology, Umeå University, Umeå, Sweden.
¹³ Anaesthesiology and Intensive Care Medicine, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹⁴ Hedenstierna Laboratory, CIRRUS, Anaesthesiology and Intensive Care Medicine, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹⁵ Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
¹⁶ Gerald Bronfman Department of Oncology, McGill University, Montréal, Quebec, Canada.
¹⁷ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
¹⁸ Computational Medicine, Berlin Institute of Health, Charité University Medicine Berlin, Berlin, Germany.
¹⁹ Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
²⁰ Departments of Medicine and Oncology, McGill University, Montréal, Quebec, Canada.
²¹ Department of Medicine, Université de Montréal, Montréal, Quebec, Canada.
²² Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Quebec, Canada. brent.richards@mcgill.ca.
²³ Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Quebec, Canada. brent.richards@mcgill.ca.
²⁴ Department of Human Genetics, McGill University, Montréal, Quebec, Canada. brent.richards@mcgill.ca.
²⁵ Department of Twin Research, King's College London, London, UK. brent.richards@mcgill.ca.

^# Contributed equally.

PMID: 33633408
DOI: 10.1038/s41591-021-01281-1

Abstract

To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10^-8), hospitalization (OR = 0.61, P = 8 × 10^-8) and susceptibility (OR = 0.78, P = 8 × 10^-6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.

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A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity

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A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity

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