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Cruz, R.* ; Almeida, S.D.* ; Heredia, M.L.* ; Quintela, I.* ; Ceballos, F.C.* ; Pita, G.* ; Lorenzo-Salazar, J.M.* ; González-Montelongo, R.* ; Gago-Dominguez, M.* ; Porras, M.S.* ; Castaño, J.A.T.* ; Nevado, J.* ; Aguado, J.M.* ; Aguilar, C.* ; Aguilera-Albesa, S.* ; Almadana, V.* ; Almoguera, B.* ; Alvarez, N.* ; Andreu-Bernabeu,* ; Arana-Arri, E.* ; Arango, C.* ; Arranz, M.J.* ; Artiga, M.J.* ; Baptista-Rosas, R.C.* ; Barreda-Sánchez, M.* ; Belhassen-Garcia, M.* ; Bezerra, J.F.* ; Bezerra, M.A.C.* ; Boix-Palop, L.* ; Brion, M.* ; Brugada, R.* ; Bustos, M.* ; Calderón, E.J.* ; Carbonell, C.* ; Castelao, J.E.* ; Conde-Vicente, R.* ; Cordero-Lorenzana, M.L.* ; Cortes-Sanchez, J.L.* ; Corton, M.* ; Darnaude, M.T.* ; De Martino-Rodríguez, A.* ; Campo-Pérez, V.* ; Bustamante, A.D.* ; Domínguez-Garrido, E.* ; Luchessi, A.D.* ; Eirós, R.* ; Sanabria, G.M.E.* ; Fariñas, M.C.* ; Fernández-Robelo, U.* ; Fernández-Rodríguez, A.* ; Fernández-Villa, T.* ; Gil-Fournier, B.* ; Gómez-Arrue, J.* ; Álvarez, B.G.* ; Quirós, F.G.B.* ; González-Peñas, J.* ; Gutiérrez-Bautista, J.F.* ; Herrero, M.J.* ; Herrero-Gonzalez, A.* ; Jimenez-Sousa, M.A.* ; Lattig, M.C.* ; Borja, A.L.* ; Lopez-Rodriguez, R.* ; Mancebo, E.* ; Martín-López, C.* ; Martín, V.* ; Martinez-Nieto, O.* ; Martinez-Lopez, I.* ; Martinez-Resendez, M.F.* ; Martinez-Perez,* ; Mazzeu, J.A.* ; Macías, E.M.* ; Minguez, P.* ; Cuerda, V.M.* ; Silbiger, V.N.* ; Oliveira, S.F.* ; Ortega-Paino, E.* ; Parellada, M.* ; Paz-Artal, E.* ; Santos, N.P.C.* ; Pérez-Matute, P.* ; Perez, P.* ; Pérez-Tomás, M.E.* ; Perucho, T.* ; Pinsach-Abuin, M.L.* ; Pompa-Mera, E.N.* ; Porras-Hurtado, G.L.* ; Pujol, A.* ; León, S.R.* ; Resino, S.* ; Fernandes, M.R.* ; Rodríguez-Ruiz, E.* ; Rodriguez-Artalejo, F.* ; Rodriguez-Garcia, J.A.* ; Ruiz-Cabello, F.* ; Ruiz-Hornillos, J.* ; Ryan, P.* ; Soria, J.M.* ; Souto, J.C.* ; Tamayo, E.* ; Tamayo-Velasco, A.* ; Taracido-Fernandez, J.C.* ; Teper, A.* ; Torres-Tobar, L.* ; Urioste, M.* ; Valencia-Ramos, J.* ; Yáñez, Z.* ; Zarate, R.* ; Pigazzini, S.* ; Degenhardt, F.* ; Butler-Laporte, G.* ; Maya-Miles, D.* ; Bujanda, L.* ; Bouysran, Y.* ; Palom, A.* ; Ellinghaus, D.* ; Martínez-Bueno, M.* ; Rolker, S.* ; Amitrano, S.* ; Roade, 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.* ; 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, B.* ; Ganna, A.* ; Boada, M.* ; Rojas, I.* ; Ruiz, A.* ; Sanchez, P.* ; Real, L.M.* ; Guillén-Navarro, E.* ; Ayuso, C.* ; González-Neira, A.* ; Riancho, J.A.* ; Rojas-Martinez, A.* ; Carracedo, A.* ; Lapunzina, P.*

Novel genes and sex differences in COVID-19 severity.

Hum. Mol. Genet. 31, 3789-3806 (2022)

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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 < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). 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 = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), 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 = 4.1x10-8). 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.

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