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

By Tomoko Nakanishi, Sara Pigazzini, Frauke Degenhardt, Mattia Cordioli, Guillaume Butler-Laporte, Douglas Maya-Miles, Beatriz Nafr_a-Jim_nez, Youssef Bouysran, Mari EK Niemi, Adriana Palom, David Ellinghaus, Atlas Khan, Manuel Mart_nez-Bueno, Selina Rolker, Sara Amitano, Luisa Roade, FinnGen, The COVID-19 Host Genetics Initiative, Francesca Fava, Christoph D. Spinner, Daniele Prati, David Bernardo, Federico Garcia, Darcis Gilles, Israel Fernandez-Cadenas, Jan Cato Holter, Jesus Banales, Robert Frithiof, Krzysztof Kiryluk, Stefano Duga, Rosanna Asselta, Alexandre C Pereira, Manuel Romero-Gomez, Luis Bujanda, Johannes R. Hov, Isabelle Migeotte, Alessandra Renieri, Anna M Planas, Kerstin U Ludwig, Maria Buti, Souad Rahmouni, Marta E. Alarc_n-Riquelme, Eva C Schulte, Andre Franke, Tom H. Karlsen, Luca Valenti, Hugo J Zeberg, J. Brent Richards, andrea ganna

Posted 12 Mar 2021
medRxiv DOI: 10.1101/2021.03.07.21252875

Background: 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. Method: 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. Findings: 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. Interpretation: 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: Funding was obtained by each of the participating cohorts individually.

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