1. A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity
- Author
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David R. Morrison, Elsa Brunet-Ratnasingham, Marc Afilalo, Nardin Rezk, Michael Hultström, Maik Pietzner, Hugo Zeberg, Tala Abdullah, Nicola D. Kerrison, Daniel Kaufmann, Celia M. T. Greenwood, Tomoko Nakanishi, Guillaume Butler-Laporte, Elin Thysell, Claudia Langenberg, Kaiqiong Zhao, Danielle Henry, Michaël Chassé, Vincenzo Forgetta, Madeleine Durand, Miklos Lipcsey, Clare Paterson, Michael Pollak, Jonathan Afilalo, Yiheng Chen, Vincent Mooser, Xiaoqing Xue, Zaman Afrasiabi, Louis Petitjean, Meriem Bouab, J. Brent Richards, Johan Normark, Branka Vulesevic, Nofar Kimchi, Charlotte Guzman, Noor Almamlouk, Chris Tselios, Sirui Zhou, Robert Frithiof, Olumide Adeleye, and Laetitia Laurent
- Subjects
0301 basic medicine ,Innate immune system ,business.industry ,Confounding ,Case-control study ,Mendelian Randomization Analysis ,General Medicine ,Odds ratio ,Quantitative trait locus ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Severity of illness ,Mendelian randomization ,Immunology ,Medicine ,business - 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. A variant of the OAS1 gene, which encodes an enzyme that is critical for the innate immune response to viral infections, is associated with decreased risk of death in patients with COVID-19.
- Published
- 2021
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