Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality.

Tomoko Nakanishi, Sara Pigazzini, Frauke Degenhardt, Mattia Cordioli, Guillaume Butler-Laporte, Douglas Maya-Miles, Luis Bujanda, Youssef Bouysran, Mari Ek Niemi, Adriana Palom, David Ellinghaus, Atlas Khan, Manuel Martínez-Bueno, Selina Rolker, Sara Amitrano, Luisa Roade Tato, Francesca Fava, Christoph D Spinner, Daniele Prati, David Bernardo, Federico Garcia, Gilles Darcis, Israel Fernandez-Cadenas, Jan Cato Holter, Jesus M Banales, Robert Frithiof, Krzysztof Kiryluk, Stefano Duga, Rosanna Asselta, Alexandre C Pereira, Manuel Romero-Gómez, Beatriz Nafría-Jiménez, Johannes R Hov, Isabelle Migeotte, Alessandra Renieri, Anna M Planas, Kerstin U Ludwig, Maria Buti, Souad Rahmouni, Marta E Alarcón-Riquelme, Eva C Schulte, Andre Franke, Tom H Karlsen, Luca Valenti, Hugo Zeberg, J Brent Richards, Andrea Ganna
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The journal of clinical investigation
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<h4>Background</h4>There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition.<h4>Methods</h4>We combined individual level data from 13,888 COVID-19 patients (N=7,185 hospitalized) from 17 cohorts in nine countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications and laboratory values. We next performed meta-analyses using FinnGen and the Columbia University COVID-19 Biobank.<h4>Results</h4>We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR 1.4, 95%CI 1.2-1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR 2.1, 95%CI 1.6-2.6), venous thromboembolism (OR 1.7, 95%CI 1.2-2.4), and hepatic injury (OR 1.5, 95%CI 1.2-2.0). Risk allele carriers ≤60 years had higher odds of death or severe respiratory failure (OR 2.7, 95%CI 1.8-3.9) compared to those >60 years (OR 1.5, 95%CI 1.2-1.8, interaction-p=0.038). Amongst individuals ≤60 years who died or experienced severe respiratory failure, 32.3% were risk variant carriers, compared to 13.9% of those not experiencing these outcomes. The genetic risk improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors.<h4>Conclusions</h4>The major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced amongst individuals ≤60 years. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.