Journal Article

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

Lipcsey, Miklós, Afilalo, Jonathan, Vulesevic, Branka, Afilalo, Marc, Zhao, Kaiqiong, Adeleye, Olumide, Afrasiabi, Zaman, Thysell, Elin, Langenberg, Claudia, Nakanishi, Tomoko, Chen, Yiheng, Greenwood, Celia M. T., Petitjean, Louis, Hultström, Michael, Normark, Johan, Laurent, Laetitia, Zeberg, Hugo, Xue, Xiaoqing, Mooser, Vincent, Richards, J. Brent, Butler-Laporte, Guillaume, Guzman, Charlotte, Chassé, Michaël, Tselios, Chris, Zhou, Sirui, Bouab, Meriem, Pollak, Michael, Durand, Madeleine, Forgetta, Vincenzo, Frithiof, Robert, Almamlouk, Noor, Pietzner, Maik, Kimchi, Nofar, Paterson, Clare, Abdullah, Tala, Brunet-Ratnasingham, Elsa, Henry, Danielle, Kaufmann, Daniel E., Morrison, David R., Kerrison, Nicola, Rezk, Nardin

2021

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 2',5'-Oligoadenylate Synthetase - genetics / 2',5'-Oligoadenylate Synthetase - physiology / 692/308/2056 / 692/699/255/2514 / Aged / Aged, 80 and over / Animals / Biomedical and Life Sciences / Biomedicine / Cancer Research / Case-Control Studies / Causation / Coronaviruses / COVID-19 / COVID-19 - etiology / COVID-19 - genetics / Drug development / Female / Genetic Predisposition to Disease / Hominids / Humans / Immune response / Infectious Diseases / Innate immunity / Interleukin-10 Receptor beta Subunit - genetics / Male / Mendelian Randomization Analysis / Metabolic Diseases / Middle Aged / Molecular Medicine / Neanderthals / Neurosciences / Protein Isoforms - physiology / Proteins / Quantitative Trait Loci / SARS-CoV-2 / Severity of Illness Index / Susceptibility / Viral diseases / White People