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Nakanishi, T.* ; Pigazzini, S.* ; Degenhardt, F.* ; Cordioli, M.* ; Butler-Laporte, G.* ; Maya-Miles, D.* ; Bujanda, L.* ; Bouysran, Y.* ; Niemi, M.E.* ; Palom, A.* ; Ellinghaus, D.* ; Khan, A.* ; Martínez-Bueno, M.* ; Rolker, S.* ; Amitrano, S.* ; Roade Tato, L.* ; Fava, F.* ; Spinner, C.D.* ; Prati, D.* ; Bernardo, D.* ; Garcia, F.* ; Darcis, G.* ; Fernandez-Cadenas, I.* ; Holter, J.C.* ; Banales, J.M.* ; Frithiof, R.* ; Kiryluk, K.* ; Duga, S.* ; Asselta, R.* ; Pereira, A.C.* ; Romero-Gómez, M.* ; Nafría-Jiménez, B.* ; Hov, J.R.* ; Migeotte, I.* ; Renieri, A.* ; Planas, A.M.* ; Ludwig, K.U.* ; Buti, M.* ; Rahmouni, S.* ; Alarcón-Riquelme, M.E.* ; Schulte, E.C. ; Franke, A.* ; Karlsen, T.H.* ; Valenti, L.* ; Zeberg, H.* ; Richards, J.B.* ; Ganna, A.*

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

J. Clin. Invest. 131:e152386 (2021)

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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.

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