Novel genes and sex differences in COVID-19 severity
Authors: Cruz Raquel , Diz-de Almeida Silvia , López de Heredia Miguel , Quintela Inés , Ceballos Francisco C , Pita Guillermo , Lorenzo-Salazar José M , González-Montelongo Rafaela , Gago-Domínguez Manuela , Sevilla Porras Marta , Tenorio Castaño Jair Antonio , Nevado Julian , Aguado Jose María , Aguilar Carlos , Aguilera-Albesa Sergio , Almadana Virginia , Almoguera Berta , Alvarez Nuria , Andreu-Bernabeu Álvaro , Arana-Arri Eunate , Arango Celso , Arranz María J , Artiga Maria-Jesus , Baptista-Rosas Raúl C , Barreda-Sánchez María , Belhassen-Garcia Moncef , Bezerra Joao F , Bezerra Marcos A C , Boix-Palop Lucía , Brion María , Brugada Ramón , Bustos Matilde , Calderón Enrique J , Carbonell Cristina , Castano Luis , Castelao Jose E , Conde-Vicente Rosa , Cordero-Lorenzana M Lourdes , Cortes-Sanchez Jose L , Corton Marta , Darnaude M Teresa , De Martino-Rodríguez Alba , del Campo-Pérez Victor , Diaz de Bustamante Aranzazu , Domínguez-Garrido Elena , Luchessi Andre D , Eiros Rocío , Estigarribia Sanabria Gladys Mercedes , Carmen Fariñas María , Fernández-Robelo Uxía , Fernández-Rodríguez Amanda , Fernández-Villa Tania , Gil-Fournier Belén , Gómez-Arrue Javier , González Álvarez Beatriz , Gonzalez Bernaldo de Quirós Fernan , González-Peñas Javier , Gutiérrez-Bautista Juan F , Herrero María José , Herrero-Gonzalez Antonio , Jimenez-Sousa María A , Lattig María Claudia , Liger Borja Anabel , Lopez-Rodriguez Rosario , Mancebo Esther , Martín-López Caridad , Martín Vicente , Martinez-Nieto Oscar , Martinez-Lopez Iciar , Martinez-Resendez Michel F , Martinez-Perez Angel , Mazzeu Juliana F , Merayo Macías Eleuterio , Minguez Pablo , Moreno Cuerda Victor , Silbiger Vivian N , Oliveira Silviene F , Ortega-Paino Eva , Parellada Mara , Paz-Artal Estela , Santos Ney P C , Pérez-Matute Patricia , Perez Patricia , Pérez-Tomás M Elena , Perucho Teresa , Pinsach-Abuin Mel Lina , Pompa-Mera Ericka N , Porras-Hurtado Gloria L , Pujol Aurora , Ramiro León Soraya , Resino Salvador , Fernandes Marianne R , Rodríguez-Ruiz Emilio , Rodriguez-Artalejo Fernando , Rodriguez-Garcia José A , Ruiz Cabello Francisco , Ruiz-Hornillos Javier , Ryan Pablo , Soria José Manuel , Souto Juan Carlos , Tamayo Eduardo , Tamayo-Velasco Alvaro , Taracido-Fernandez Juan Carlos , Teper Alejandro , Torres-Tobar Lilian , Urioste Miguel , Valencia-Ramos Juan , Yáñez Zuleima , Zarate Ruth , Nakanishi Tomoko , Pigazzini Sara , Degenhardt Frauke , Butler-Laporte Guillaume , Maya-Miles Douglas , Bujanda Luis , Bouysran Youssef , Palom Adriana , Ellinghaus David , Martínez-Bueno Manuel , Rolker Selina , Amitrano Sara , Roade Luisa , Fava Francesca , Spinner Christoph D , Prati Daniele , Bernardo David , Garcia Federico , Darcis Gilles , Fernández-Cadenas Israel , Holter Jan Cato , Banales Jesus M , Frithiof Robert , Duga Stefano , Asselta Rosanna , Pereira Alexandre C , Romero-Gómez Manuel , Nafría-Jiménez Beatriz , 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 Brent , Ganna Andrea , Boada Mercè , de Rojas Itziar , Ruiz Agustín , Sánchez-Juan Pascual , Real Luis Miguel ,   SCOURGE Cohort Group,   HOSTAGE Cohort Group,   GRA@CE Cohort Group, Guillen-Navarro Encarna , Ayuso Carmen , González-Neira Anna , Riancho José A , Rojas-Martinez Augusto , Flores Carlos , Lapunzina Pablo , Carracedo Angel 
Published: June 2022

Abstract
Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (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 &lt; 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 (HGI) 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 (&lt;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.