Novel genes and sex differences in COVID-19 severity.
Authors
Raquel Cruz, Silvia Diz-de Almeida, Miguel López Heredia, Inés Quintela, Francisco C Ceballos, Guillermo Pita, José M Lorenzo-Salazar, Rafaela González-Montelongo, Manuela Gago-Domínguez, Marta Sevilla Porras, Jair Antonio Tenorio Castaño, Julian Nevado, Jose María Aguado, Carlos Aguilar, Sergio Aguilera-Albesa, Virginia Almadana, Berta Almoguera, Nuria Alvarez, Álvaro Andreu-Bernabeu, Eunate Arana-Arri, Celso Arango, María J Arranz, Maria-Jesus Artiga, Raúl C Baptista-Rosas, María Barreda-Sánchez, Moncef Belhassen-Garcia, Joao F Bezerra, Marcos A C Bezerra, Lucía Boix-Palop, María Brion, Ramón Brugada, Matilde Bustos, Enrique J Calderón, Cristina Carbonell, Luis Castano, Jose E Castelao, Rosa Conde-Vicente, M Lourdes Cordero-Lorenzana, Jose L Cortes-Sanchez, Marta Corton, M Teresa Darnaude, Alba De Martino-Rodríguez, Victor Campo-Pérez, Aranzazu Diaz Bustamante, Elena Domínguez-Garrido, Andre D Luchessi, Rocío Eirós, Gladys Mercedes Estigarribia Sanabria, María Carmen Fariñas, Uxía Fernández-Robelo, Amanda Fernández-Rodríguez, Tania Fernández-Villa, Belén Gil-Fournier, Javier Gómez-Arrue, Beatriz González Álvarez, Fernan Gonzalez Bernaldo Quirós, Javier González-Peñas, Juan F Gutiérrez-Bautista, María José Herrero, Antonio Herrero-Gonzalez, María A Jimenez-Sousa, María Claudia Lattig, Anabel Liger Borja, Rosario Lopez-Rodriguez, Esther Mancebo, Caridad Martín-López, Vicente Martín, Oscar Martinez-Nieto, Iciar Martinez-Lopez, Michel F Martinez-Resendez, Ángel Martinez-Perez, Juliana A Mazzeu, Eleuterio Merayo Macías, Pablo Minguez, Victor Moreno Cuerda, Vivian N Silbiger, Silviene F Oliveira, Eva Ortega-Paino, Mara Parellada, Estela Paz-Artal, Ney P C Santos, Patricia Pérez-Matute, Patricia Perez, M Elena Pérez-Tomás, Teresa Perucho, Mel Lina Pinsach-Abuin, Ericka N Pompa-Mera, Gloria L Porras-Hurtado, Aurora Pujol, Soraya Ramiro León, Salvador Resino, Marianne R Fernandes, Emilio Rodríguez-Ruiz, Fernando Rodriguez-Artalejo, José A Rodriguez-Garcia, Francisco Ruiz-Cabello, Javier Ruiz-Hornillos, Pablo Ryan, José Manuel Soria, Juan Carlos Souto, Eduardo Tamayo, Alvaro Tamayo-Velasco, Juan Carlos Taracido-Fernandez, Alejandro Teper, Lilian Torres-Tobar, Miguel Urioste, Juan Valencia-Ramos, Zuleima Yáñez, Ruth Zarate, Tomoko Nakanishi, Sara Pigazzini, Frauke Degenhardt, Guillaume Butler-Laporte, Douglas Maya-Miles, Luis Bujanda, Youssef Bouysran, Adriana Palom, David Ellinghaus, Manuel Martínez-Bueno, Selina Rolker, Sara Amitrano, Luisa Roade, Francesca Fava, Christoph D Spinner, Daniele Prati, David Bernardo, Federico Garcia, Gilles Darcis, Israel Fernández-Cadenas, Jan Cato Holter, Jesus M Banales, Robert Frithiof, Stefano Duga, Rosanna Asselta, Alexandre C Pereira, Manuel Romero-Gómez, Beatriz Nafría-Jiménez, Johannes R Hov, Isabelle Migeotte, Alessandra Renieri, Anna M Planas, Kerstin U Ludwig, Maria Buti, Souad Rahmouni, Marta E Alarcón-Riquelme, Eva C Schulte, Andre Franke, Tom H Karlsen, Luca Valenti, Hugo Zeberg, Brent Richards, Andrea Ganna, Mercè Boada, Itziar Rojas, Agustín Ruiz, Pascual Sánchez, Luis Miguel Real, Encarna Guillen-Navarro, Carmen Ayuso, Anna González-Neira, José A Riancho, Augusto Rojas-Martinez, Carlos Flores, Pablo Lapunzina, Ángel Carracedo
Year of publication
2022Journal
HUM MOL GENETVolume
-Issue
-Abstract
Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5×10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3×10-22 and p = 8.1×10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4×10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7×10-8) and ARHGAP33 (p = 1.3×10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1×10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.