Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality
Authors: Nakanishi Tomoko , Pigazzini Sara , Degenhardt Frauke , Cordioli Mattia , Butler-Laporte Guillaume , Maya-Miles Douglas , Nafría-Jiménez Beatriz , Bouysran Youssef , Niemi Mari , Palom Adriana , Ellinghaus David , Khan Atlas , Martínez-Bueno Manuel , Rolker Selina , Amitano Sara , Tato Luisa Roade ,   FinnGen,   The COVID-19 Host Genetics Initiative, Fava Francesca , Spinner Christoph D. , Prati Daniele , Bernardo David , Garcia Federico , Darcis Gilles , Fernández-Cadenas Israel , Holter Jan Cato , Banales Jesus , Frithiof Robert , Kiryluk Krzysztof , Duga Stefano , Asselta Rosanna , Pereira Alexandre C , Romero-Gómez Manuel , Bujanda Luis , 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 
Published: March 2021

AbstractBackgroundThere 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.MethodThe 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.FindingsWe 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.InterpretationThe 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.FundingFunding was obtained by each of the participating cohorts individually.