%0 Journal Article
%A Nakanishi, Tomoko
%A Pigazzini, Sara
%A Degenhardt, Frauke
%A Cordioli, Mattia
%A Butler-Laporte, Guillaume
%A Maya-Miles, Douglas
%A Nafría-Jiménez, Beatriz
%A Bouysran, Youssef
%A Niemi, Mari
%A Palom, Adriana
%A Ellinghaus, David
%A Khan, Atlas
%A Martínez-Bueno, Manuel
%A Rolker, Selina
%A Amitano, Sara
%A Tato, Luisa Roade
%A FinnGen, The COVID-19 Host Genetics Initiative
%A Fava, Francesca
%A Spinner, Christoph D
%A Prati, Daniele
%A Bernardo, David
%A Garcia, Federico
%A Darcis, Gilles
%A Fernández-Cadenas, Israel
%A Holter, Jan Cato
%A Banales, Jesus
%A Frithiof, Robert
%A Kiryluk, Krzysztof
%A Duga, Stefano
%A Asselta, Rosanna
%A Pereira, Alexandre C
%A Romero-Gómez, Manuel
%A Bujanda, Luis
%A Hov, Johannes R
%A Migeotte, Isabelle
%A Renieri, Alessandra
%A Planas, Anna M
%A Ludwig, Kerstin U
%A Buti, Maria
%A Rahmouni, Souad
%A Alarcón-Riquelme, Marta E
%A Schulte, Eva C
%A Franke, Andre
%A Karlsen, Tom H
%A Valenti, Luca
%A Zeberg, Hugo
%A Richards, J Brent
%A Ganna, Andrea
%T Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality.
%D 2021
%U https://hdl.handle.net/10668/25276
%X There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2-1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3-1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality-and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management. Funding was obtained by each of the participating cohorts individually.
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