New susceptibility loci for severe COVID-19 by detailed GWAS analysis in European populations

Degenhardt, F.; Ellinghaus, D.; Juzenas, S.; Lerga-Jaso, J.; Wendorff, M.; Maya-Miles, D.; Uellendahl-Werth, F.; ElAbd, H.; Ruehlemann, M. C.; Arora, J.; oezer, O.; Lenning, O. B.; Myhre, R.; Vadla, M. S.; Wacker, E. M.; Wienbrandt, L.; Blandino Ortiz, A.; de Salazar, A.; Garrido Chercoles, A.; Palom, A.; Ruiz, A.; Mantovani, A.; Zanella, A.; Rygh Holten, A.; Mayer, A.; Bandera, A.; Cherubini, A.; Protti, A.; Aghemo, A.; Gerussi, A.; Popov, A.; Ramirez, A.; Braun, A.; Nebel, A.; Barreira, A.; Lleo, A.; Teles, A.; Kildal, A. B.; Biondi, A.; Ganna, A.; Gori, A.; Glueck, A.; Lind, A.; Hinney, A.

Due to the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), deepening the host genetic contribution to severe COVID-19 may further improve our understanding about underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany, as well as hypothesis-driven targeted analysis of the human leukocyte antigen (HLA) region and chromosome Y haplotypes. We include detailed stratified analyses based on age, sex and disease severity. In addition to already established risk loci, our data identify and replicate two genome-wide significant loci at 17q21.31 and 19q13.33 associated with severe COVID-19 with respiratory failure. These associations implicate a highly pleiotropic ~0.9-Mb 17q21.31 inversion polymorphism, which affects lung function and immune and blood cell counts, and the NAPSA gene, involved in lung surfactant protein production, in COVID-19 pathogenesis.