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

Frauke C. Degenhardt; David Ellinghaus; Simonas Juzėnas; Jon Lerga-Jaso; Mareike Wendorff; Douglas Maya‐Miles; Florian Uellendahl-Werth; Hesham ElAbd; Malte Christoph Rühlemann; Jatin Arora; Onur Özer; Ole Bernt Lenning; Ronny Myhre; May Sissel Vadla; Eike Matthias Wacker; Lars Wienbrandt; Aaron Blandino Ortíz; Adolfo de Salazar; Adolfo Garrido Chercoles; Adriana Palom; Agustı́n Ruiz; Alba-Estela Garcia-Fernandez; Albert Blanco‐Grau; Alberto Mantovani; Alberto Zanella; Aleksander Rygh Holten; Alena Mayer; Alessandra Bandera; Alessandro Cherubini; Alessandro Protti

doi:10.1093/hmg/ddac158

Genetic & Genomic MedicineHuman Molecular GeneticsJul 15, 2022

Peer-reviewed journal article

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

Frauke C. Degenhardt iD, David Ellinghaus iD, Simonas Juzėnas iD, Jon Lerga-Jaso iD, Mareike Wendorff iD, Douglas Maya‐Miles, Florian Uellendahl-Werth iD, Hesham ElAbd iD, Malte Christoph Rühlemann iD, Jatin Arora iD, Onur Özer iD, Ole Bernt Lenning iD, Ronny Myhre iD, May Sissel Vadla iD, Eike Matthias Wacker iD, Lars Wienbrandt iD, Aaron Blandino Ortíz iD, Adolfo de Salazar iD, Adolfo Garrido Chercoles, Adriana Palom iD, Agustı́n Ruiz iD, Alba-Estela Garcia-Fernandez iD, Albert Blanco‐Grau iD, Alberto Mantovani iD, Alberto Zanella iD, , Elio Scarpini

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Abstract

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic [~]0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.