* SCOURGE Cohort Group Javier Abellan15,16; René Acosta-Isaac17; Jose María Aguado18,19,20,21; Carlos Aguilar22; Sergio Aguilera-Albesa23,24; Abdolah Ahmadi Sabbagh25; Jorge Alba26; Sergiu Albu27,28,29; Karla A.M. Alcalá-Gallardo30; Julia Alcoba-Florez31; Sergio Alcolea Batres32; Holmes Rafael AlgarinLara33,34; Virginia Almadana35; Kelliane A. Medeiros36,37; Julia Almeida38,39; Berta Almoguera40,3; María R. Alonso41; Nuria Alvarez41; Rodolfo Alvarez-Sala Walther32; Yady Álvarez-Benítez33,34; Felipe Álvarez-Navia42,43; Katiusse A. dos Santos44; Álvaro Andreu-Bernabeu45,20; Maria Rosa Antonijoan46; Eleno Martínez-Aquino47; Eunate Arana-Arri48,49; Carlos Aranda50,51; Celso Arango45,52,20; Carolina Araque53,54; Nathalia K. Araujo55; Ana C. Arcanjo56,57,58; Ana Arnaiz59,60; Francisco Arnalich Fernández61; María J. Arranz62; José Ramon Arribas Lopez61; Maria-Jesus Artiga63; Yubelly Avello-Malaver64; Carmen Ayuso40,3; Belén Ballina Martín25; Raúl C. BaptistaRosas65,66,67; Ana María Baldion64; Andrea Barranco-Díaz34; María Barreda- Sánchez68,69; Viviana Barrera-Penagos64; Moncef Belhassen-Garcia70,43; David Bernal-Bello71; Enrique Bernal68; Joao F. Bezerra72; Marcos A.C. Bezerra73; Natalia Blanca-López74; Rafael Blancas75; Lucía Boix-Palop76; Alberto Borobia77; Elsa Bravo78; María Brion79,80; Óscar Brochado-Kith81; Ramón Brugada82,83,80,84; Matilde Bustos85; Alfonso Cabello86; Alejandro Cáceres4,5; Juan J. Caceres-Agra87; Esther Calbo76; Enrique J. Calderón88,6,89; Shirley Camacho90; Francisco C. Ceballos81; Yolanda Cañadas51; Cristina Carbonell42,43; Servando Cardona-Huerta91; Maria Sanchez Carpintero50,51; Carlos Carpio Segura32; José Antonio Carrillo-Avila92; Marcela C. Campos56; Carlos Casasnovas93,94,3; Luis Castano48,95,3,96,97; Carlos F. Castaño50,51; Jose E. Castelao98; Aranzazu Castellano Candalija99; María A. Castillo90; Walter G. ChavesSantiago100,54; Sylena Chiquillo-Gómez33,34; Marco A. Cid-Lopez30; Oscar CienfuegosJimenez91; Rosa Conde-Vicente101; Gabriela C.R. Cunha102; M. Lourdes Cordero-Lorenzana103; Dolores Corella104,105; Almudena Corrales106,107; Jose L. Cortes-Sanchez91,108; Marta Corton40,3; Karla S.C. Souza109; Fabiola T.C. Silva56; Raquel Cruz8,3,9,10; Luisa Cuesta110; Nathali A.C. Tavares111; Maria C.C. Carvalho112; David Dalmau62,76; Raquel C.S. Dantas-Komatsu113; M. Teresa Darnaude114; Raimundo de Andrés115; Carmen de Juan116; Juan De la Cruz Troca117,118,6; Carmen de la Horra89; Ana B. de la Hoz48; Alba De Martino-Rodríguez119,120; Marina S. Cruz121; Julianna Lys de Sousa Alves Neri122; Victor del Campo-Pérez123; Juan Delgado-Cuesta124; Aranzazu Diaz de Bustamante114; Anderson Díaz-Pérez34; Beatriz Dietl76; Silvia Diz-de Almeida3,10; Manoella do Monte Alves125,126; Elena Domínguez-Garrido127; Lidia S. Rosa128; Andre D. Luchessi129; Jose Echave-Sustaeta130; Rocío Eiros131; César O. EncisoOlivera53,54; Gabriela Escudero132; Pedro Pablo España133; Gladys Mercedes Estigarribia Sanabria134; María Carmen Fariñas59,60,135; Ramón Fernández59,136; Lidia FernandezCaballero40,3; Ana Fernández-Cruz137; Silvia Fernández Ferrero25; Yolanda Fernández Martínez25; María J. Fernandez-Nestosa138; Uxía Fernández-Robelo139; Amanda FernándezRodríguez81; Marta Fernández-Sampedro59,135,60; Ruth Fernández40,3; Tania Fernández-Villa140; Carmen Fernéndez Capitán99; Antonio Augusto F. Carioca141; Patricia Flores-Pérez142; Lácides Fuenmayor-Hernández34; Marta Fuertes Núñez25; Victoria Fumadó143; Ignacio Gadea144; Lidia Gagliardi50,51; Manuela Gago-Domínguez13,9; Natalia Gallego11; Cristina Galoppo145; Ana García-Soidán146; Carlos Garcia Cerrada15,16; Aitor García-de-Vicuña48,95; Josefina GarciaGarcía68; Irene García-García77; Carmen García-Ibarbia59,135,60; Andrés C. García-Montero147; Leticia García50,51; Mercedes García50,51; María Carmen García Torrejón148,16; Inés García40,3; Elisa García-Vázquez68; Emiliano Garza-Frias91; Angela Gentile145; Belén Gil-Fournier149; Jéssica N.G. de Araújo150; Mario Gómez-Duque100,54; Javier Gómez-Arrue119,120; Luis Gómez Carrera32; María Gómez García151; Ángela Gómez Sacristán152; Juan R. González4,5,6,14; Anna González-Neira41; Beatriz González Álvarez119,120; Fernan Gonzalez Bernaldo de Quirós153; Rafaela González-Montelongo154; Javier González-Peñas45,20,52; Manuel Gonzalez-Sagrado101; Hugo Gonzalo Benito155; Oscar Gorgojo-Galindo156; Miguel Górgolas86; Florencia Guaragna145; Jessica G. Chaux54; Encarna Guillen-Navarro68,157,158,159; Beatriz Guillen-Guio106; Pablo Guisado-Vasco130; Luz D. Gutierrez-Castañeda160,54; Juan F. Gutiérrez-Bautista161; Sara HeiliFrades162; Rafael H. Jacomo163; Estefania Hernandez164; Cristina Hernández Moro25; Luis D. Hernandez-Ortega165,166; Guillermo Hernández-Pérez42; Rebeca Hernández-Vaquero167; Belen Herraez41; M. Teresa Herranz68; María Herrera50,51; María José Herrero168,169; Antonio HerreroGonzalez170; Juan P. Horcajada171,172,28,173; Natale Imaz-Ayo48; Maider IntxaustiUrrutibeaskoa174; Antonio Íñigo-Campos154; María Íñiguez175; Rubén Jara68; Ángel Jiménez50,51; Ignacio Jiménez-Alfaro176; Pilar Jiménez161; María A. Jimenez-Sousa81; Iolanda Jordan177,178,6; Rocío Laguna-Goya179,180; Daniel Laorden32; María Lasa-Lazaro179,180; María Claudia Lattig90,181; Ailen Lauriente145; Anabel Liger Borja182; Lucía Llanos183; Amparo López-Bernús42,43; Miguel It is made available under a CC-BY-NC-ND 4.0 International license . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. medRxiv preprint doi: https://doi.org/10.1101/2020.04.19.20071357; this version posted February 18, 2022. The copyright holder for this preprint López de Heredia3 ; Esther Lopez-Garcia117,118,6,184; Eduardo López Granados185,186,3; Rosario Lopez-Rodriguez40,3; Miguel A. López-Ruz187,188,189; Leonardo Lorente190; José M. LorenzoSalazar154; José E. Lozano191; María Lozano-Espinosa182; Ignacio Mahillo192,193,107; Esther Mancebo179,180; Carmen Mar133; Cristina Marcelo Calvo99; Alba Marcos-Delgado194; Miguel Marcos42,43; Alicia Marín Candon77; Pablo Mariscal Aguilar32; Laura Martin-Pedraza74; Marta Martin-Fernandez195; Caridad Martín-López182; José-Ángel Martín-Oterino42,43; María Dolores Martín196; Vicente Martín194,6; María M. Martín197; María Martín-Vicente81; Amalia Martinez198; Óscar Martínez-González75; Ricardo Martínez164; Pedro Martinez-Paz155; Covadonga M. DiazCaneja45,52,20; Oscar Martinez-Nieto64,181; Iciar Martinez-Lopez199,200; Michel F. MartinezResendez91; Silvia Martínez59,135; Juan José Martinez94,3; Angel Martinez-Perez201; Andrea Martínez-Ramas40,3; Violeta Martínez Robles25; Laura Marzal40,3; Juliana F. Mazzeu202,203,204; Francisco J. Medrano88,6,89; Xose M. Meijome205,206; Natalia Mejuto-Montero207; Ingrid Mendes3 ; Alice L. Duarte109; Ana Méndez-Echevarria208; Humberto Mendoza Charris78,34; Eleuterio Merayo Macías209; Fátima Mercadillo210; Arieh R. Mercado-Sesma165,166; Pablo Minguez40,3; Elena Molina-Roldán211; Antonio J J. Molina194; Juan José Montoya164; Susana M.T. Pinho36,212,213; Patricia Moreira-Escriche116; Xenia Morelos-Arnedo78,34; Rocío Moreno3 ; Victor Moreno Cuerda15,16; Antonio Moreno-Docón68; Junior Moreno-Escalante34; Alberto Moreno Fernández99; Patricia Muñoz García214,107,20; Pablo Neira145; Julian Nevado3,11,12; Israel NietoGañán146; Vivian N. Silbiger129; Rocio Nuñez- Torres41; Antònia Obrador-Hevia215,216; J. Gonzalo Ocejo-Vinyals59,135; Virginia Olivar145; Silviene F. Oliveira56,217,204,218; Lorena Ondo40,3; Alberto Orfao38,39; Eva Ortega-Paino63; Luis Ortega219; Rocio Ortiz-Lopez91; Fernando Ortiz-Flores59,135; José A. Oteo26,175; Manuel Pacheco164; Fredy Javier Pacheco-Miranda34; Irene Padilla Conejo25; Sonia Panadero-Fajardo92; Mara Parellada45,52,20; Roberto Pariente-Rodríguez146; Vicente Friaza6,89; Estela Paz-Artal179,180,220; Germán Peces-Barba221,107; Miguel S. Pedromingo Kus222; Celia Perales144; Ney P.C. Santos223; Genilson P. Guegel224; Perez Maria Jazmin145; Alexandra Perez82,80; Patricia Pérez-Matute175; César Pérez225; Gustavo Perez-de-Nanclares48,95; Felipe Pérez-García226,227; Patricia Perez228; Luis A. Pérez-Jurado1,2,3; M. Elena Pérez-Tomás68; Teresa Perucho229; Lisbeth A. Pichardo25; Adriana P. Ribeiro36,37,213; Mel·lina Pinsach-Abuin82,80; Luz Adriana Pinzón100,54; Jeane F.P. Medeiros230; Guillermo Pita41; Francesc Pla-Junca231,3; Laura Planas-Serra94,3; Ericka N. Pompa-Mera232; Gloria L. Porras-Hurtado164; Aurora Pujol94,3,233; María Eugenia Quevedo Chávez33,34; Maria Angeles Quijada46,234; Inés Quintela8 ; Soraya Ramiro León149; Pedro Rascado Sedes235; Joana F.R. Nunes56; Delia Recalde119,120; Emma Recio-Fernández175; Salvador Resino81; Renata R. Sousa213,236; Carlos S. RivadeneiraChamorro54; Diana Roa-Agudelo64; Montserrat Robelo Pardo235; Marianne R. Fernandes223,237; María A. Rodriguez-Hernandez85; Agustí Rodriguez-Palmero238,94; Emilio Rodríguez-Ruiz235,9; Marilyn Johanna Rodriguez54; Fernando Rodriguez-Artalejo117,118,6,184; Marena RodríguezFerrer34; Carlos Rodriguez-Gallego239,240; José A. Rodriguez-Garcia25; Belén Rodríguez Maya15; Antonio Rodriguez-Nicolas161; German Ezequiel Rodriguez Novoa145; Paula A. RodriguezUrrego64; Federico Rojo241,242; Andrea Romero-Coronado34; Rubén Morilla89,243; Filomeno Rondón García25; Antonio Rosales-Castillo244; Cladelis Rubio245; María Rubio Olivera50,51; Francisco Ruiz-Cabello161,188,246; Eva Ruiz-Casares229; Juan J. Ruiz-Cubillan59,135; Javier RuizHornillos247,51,248; Montserrat Ruiz94,3; Pablo Ryan249,250,251; Hector D. Salamanca53,54; Lorena Salazar-García90; Giorgina Gabriela Salgueiro Origlia 99; Anna Sangil76; Olga SánchezPernaute252; Pedro-Luis Sánchez131,43; Antonio J. Sánchez López253; Clara Sánchez-Pablo131; María Concepción Sánchez Prados32; Javier Sánchez Real25; Jorge Sánchez Redondo15,254; Cristina Sancho- Sainz174; Esther Sande255; Arnoldo Santos225; Agatha Schlüter94,3; Sonia Segovia231,256,257; Alex Serra-Llovich62; Fernando Sevil Puras22; Marta Sevilla Porras3,11; Miguel A. Sicolo258,259; Cristina Silván Fuentes3 ; Vitor M.S. Moraes260; Vanessa S. Souza102; Jordi SoléViolán261,107; José Manuel Soria201; Jose V. Sorlí104,105; Nayara S. Silva262; Juan Carlos Souto17; John J. Sprockel100,54; José Javier Suárez-Rama8 ; David A. Suarez-Zamora64; Xiana TaboadaFraga207; Eduardo Tamayo263,156; Alvaro Tamayo-Velasco264; Juan Carlos TaracidoFernandez170; Romero H.T. Vasconcelos111; Carlos Tellería119,120; Thássia M.T. Carratto260; Jair Antonio Tenorio Castaño3,11,12; Alejandro Teper145; Izabel M.T. Araujo109; Juan Torres-Macho265; Lilian Torres-Tobar266; Ronald P. Torres Gutiérrez222; Jesús Troya249; Miguel Urioste210; Juan Valencia-Ramos267; Agustín Valido35,268; Juan Pablo Vargas Gallo269,270; Belén Varón271; Tomas Vega272; Santiago Velasco-Quirce273; Valentina Vélez-Santamaría93,94; Virginia Víctor50,51; Julia Vidán Estévez25; Gabriela V. Silva109; Miriam Vieitez-Santiago59,135; Carlos Vilches274; Lavinia Villalobos25; Felipe Villar221; Judit Villar-Garcia275,276,277; Cristina Villaverde3,40; Pablo VillosladaBlanco175; Ana Virseda-Berdices81; Tatiana X. Costa278; Zuleima Yáñez34; Antonio Zapatero Gaviria279; Ruth Zarate280; Sandra Zazo241; Carlos Flores106,107,154; José A. Riancho59,60,135; Augusto Rojas-Martinez281; Pablo Lapunzina3,11,12; Ángel Carracedo3,8,9,10,13

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) has an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome events (CME) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (CME and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, CME and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.

The authors acknowledge support from the Catalan Department of Economy and Knowledge (SGR2017/1974, SGR2017/801) and the Spanish Ministry of Science “Programa de Excelencia María de Maeztu” (MDM-2014-0370) and “Centro de Excelencia Severo Ochoa” (CEX2018-000806-S), the Fondo Europeo de Desarrollo Regional, UE (RTI2018-100789-B-I00) and the Estonian Research Council (PUT1660). Authors also receive support from the Generalitat de Catalunya through the CERCA Program.

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