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

Nakanishi, Tomoko; Pigazzini, Sara; Degenhardt, Frauke; Cordioli, Mattia; Butler-Laporte, Guillaume; Maya-Miles, Douglas; Bujanda, Luis; Bouysran, Youssef; Niemi, Mari Ek; Palom, Adriana; Ellinghaus, David; Khan, Atlas; Martínez-Bueno, Manuel; Rolker, Selina; Amitrano, Sara; Roade Tato, Luisa; Fava, Francesca; Spinner, Christoph D; Prati, Daniele; Bernardo, David; Garcia, Federico; Darcis, Gilles; Fernandez-Cadenas, Israel; Holter, Jan Cato; Banales, Jesus M; Frithiof, Robert; Kiryluk, Krzysztof; Duga, Stefano; Asselta, Rosanna; Pereira, Alexandre C; Romero-Gómez, Manuel; Nafría-Jiménez, Beatriz; Hov, Johannes R; Migeotte, Isabelle; Renieri, Alessandra; Planas, Anna M; Ludwig, Kerstin U; Buti, Maria; Rahmouni, Souad; Alarcón-Riquelme, Marta E; Schulte, Eva C; Franke, Andre; Karlsen, Tom H; Valenti, Luca; Zeberg, Hugo; Richards, J Brent; Ganna, Andrea

BACKGROUND There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition. METHODS 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. RESULTS 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. CONCLUSIONS 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.