Cruz, RaquelDiz-de Almeida, SilviaLópez Heredia, MiguelQuintela, InésCeballos, Francisco CPita, GuillermoLorenzo-Salazar, José MGonzález-Montelongo, RafaelaGago-Dominguez, ManuelaSevilla Porras, MartaTenorio Castaño, Jair AntonioNevado, JulianAguado, José MaríaAguilar, CarlosAguilera-Albesa, SergioAlmadana, VirginiaAlmoguera, BertaAlvarez, NuriaAndreu-Bernabeu, ÁlvaroArana-Arri, EunateArango, CelsoArranz, María JArtiga, Maria-JesusBaptista-Rosas, Raúl CBarreda-Sánchez, MaríaBelhassen-García, MoncefBezerra, Joao FBezerra, Marcos A CBoix-Palop, LucíaBrion, MaríaBrugada, RamónBustos, MatildeCalderón, Enrique JCarbonell, CristinaCastano, LuisCastelao, Jose EConde-Vicente, RosaCordero-Lorenzana, M LourdesCortes-Sanchez, Jose LCorton, MartaDarnaude, M TeresaDe Martino-Rodríguez, AlbaCampo-Pérez, VictorDiaz Bustamante, AranzazuDomínguez-Garrido, ElenaLuchessi, Andre DEirós, RocíoEstigarribia Sanabria, Gladys MercedesFariñas, María CarmenFernández-Robelo, UxíaFernandez-Rodriguez, AmandaFernández-Villa, TaniaGil-Fournier, BelénGómez-Arrue, JavierGonzález Álvarez, BeatrizGonzalez Bernaldo Quirós, FernanGonzález-Peñas, JavierGutiérrez-Bautista, Juan FHerrero, María JoséHerrero-Gonzalez, AntonioJimenez-Sousa, Maria AngelesLattig, María ClaudiaBorja, Anabel LigerLopez-Rodriguez, RosarioMancebo, EstherMartín-López, CaridadMartín, VicenteMartinez-Nieto, OscarMartinez-Lopez, IciarMartinez-Resendez, Michel FMartinez-Perez, AngelMazzeu, Juliana AMerayo Macías, EleuterioMinguez, PabloMoreno Cuerda, VictorSilbiger, Vivian NOliveira, Silviene FOrtega-Paino, EvaParellada, MaraPaz-Artal, EstelaSantos, Ney PCPérez-Matute, PatriciaPerez, PatriciaPérez-Tomás, M ElenaPerucho, TeresaPinsach-Abuin, Mel·linaPompa-Mera, Ericka NPorras-Hurtado, Gloria LPujol, AuroraRamiro León, SorayaResino, SalvadorFernandes, Marianne RRodríguez-Ruiz, EmilioRodríguez-Artalejo, FernandoRodriguez-Garcia, José ARuiz-Cabello, FranciscoRuiz-Hornillos, JavierRyan, PabloSoria, José ManuelSouto, Juan CarlosTamayo, EduardoTamayo-Velasco, ÁlvaroTaracido-Fernandez, Juan CarlosTeper, AlejandroTorres-Tobar, LilianUrioste, MiguelValencia-Ramos, JuanYáñez, ZuleimaZarate, RuthNakanishi, TomokoPigazzini, SaraDegenhardt, FraukeButler-Laporte, GuillaumeMaya-Miles, DouglasBujanda, LuisBouysran, YoussefPalom, AdrianaEllinghaus, DavidMartínez-Bueno, ManuelRolker, SelinaAmitrano, SaraRoade, LuisaFava, FrancescaSpinner, Christoph DPrati, DanieleBernardo, DavidGarcía, FedericoDarcis, GillesFernández-Cadenas, IsraelHolter, Jan CatoBanales, Jesus MFrithiof, RobertDuga, StefanoAsselta, RosannaPereira, Alexandre CRomero-Gómez, ManuelNafría-Jiménez, BeatrizHov, Johannes RMigeotte, IsabelleRenieri, AlessandraPlanas, Anna MLudwig, Kerstin UButi, MariaRahmouni, SouadAlarcón-Riquelme, Marta ESchulte, Eva CFranke, AndreKarlsen, Tom HValenti, LucaZeberg, HugoRichards, BrentGanna, AndreaBoada, MercèRojas, ItziarRuiz, AgustínSánchez, PascualReal, Luis MiguelGuillén-Navarro, EncarnaAyuso, CarmenGonzález-Neira, AnnaRiancho, José ARojas-Martinez, AugustoFlores, CarlosLapunzina, PabloCarracedo, ÁngelSCOURGE Cohort GroupHOSTAGE Cohort GroupGRA@CE Cohort Group2022-10-192022-10-192022-06-16Hum Mol Genet. 2022 Jun 16;ddac132.http://hdl.handle.net/20.500.12105/15073Here 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.engVoRhttp://creativecommons.org/licenses/by/4.0/Atribución 4.0 Internacional35708486ddac13210.1093/hmg/ddac1321460-2083Human molecular geneticsopen access