Novel genes and sex differences in COVID-19 severity

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 < 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 (<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.Instituto de Salud Carlos III (COV20_00622 to A.C., COV20/00792 to M.B., COV20_00181 to C.A., COV20_1144 to M.A.J.S., PI20/00876 to C.F.); European Union (ERDF) ‘A way of making Europe’. Fundación Amancio Ortega, Banco de Santander (to A.C.), Estrella de Levante S.A. and Colabora Mujer Association (to E.G.-N.) and Obra Social La Caixa (to R.B.); Agencia Estatal de Investigación (RTC-2017-6471-1 to C.F.), Cabildo Insular de Tenerife (CGIEU0000219140 ‘Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19’ to C.F.) and Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC20/57 to C.F.)

Clonal chromosomal mosaicism and loss of chromosome Y in men are risk factors for SARS-CoV-2 vulnerability in the elderly

* 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 Carracedo3,8,9,10,13The 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.N

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had 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 alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA 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, mCA 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. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Psychiatric polygenic risk as a predictor of COVID-19 risk and severity: insight into the genetic overlap between schizophrenia and COVID-19

Despite the high contagion and mortality rates that have accompanied the coronavirus disease-19 (COVID-19) pandemic, the clinical presentation of the syndrome varies greatly from one individual to another. Potential host factors that accompany greater risk from COVID-19 have been sought and schizophrenia (SCZ) patients seem to present more severe COVID-19 than control counterparts, with certain gene expression similarities between psychiatric and COVID-19 patients reported. We used summary statistics from the last SCZ, bipolar disorder (BD), and depression (DEP) meta-analyses available on the Psychiatric Genomics Consortium webpage to calculate polygenic risk scores (PRSs) for a target sample of 11,977 COVID-19 cases and 5943 subjects with unknown COVID-19 status. Linkage disequilibrium score (LDSC) regression analysis was performed when positive associations were obtained from the PRS analysis. The SCZ PRS was a significant predictor in the case/control, symptomatic/asymptomatic, and hospitalization/no hospitalization analyses in the total and female samples; and of symptomatic/asymptomatic status in men. No significant associations were found for the BD or DEP PRS or in the LDSC regression analysis. SNP-based genetic risk for SCZ, but not for BD or DEP, may be associated with higher risk of SARS-CoV-2 infection and COVID-19 severity, especially among women; however, predictive accuracy barely exceeded chance level. We believe that the inclusion of sexual loci and rare variations in the analysis of genomic overlap between SCZ and COVID-19 will help to elucidate the genetic commonalities between these conditionsThis study has been funded by Instituto de Salud Carlos III (COV20_00622 to AC) and cofunded by European Union (ERDF) “A way of making Europe”, Fundación Amancio Ortega, Banco de Santander (to AC). The contribution of the Centro National de Genotipado (CEGEN), and Centro de Supercomputación de Galicia (CESGA) for funding this project by providing supercomputing infrastructures, is also acknowledged. Authors are also particularly grateful to Banco Nacional de ADN and GRA@CE cohort group. MA was supported by a Juan de la Cierva contract (FJC2021-047538-I)

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had 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 alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA 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, mCA 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), 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). The SCOURGE study has been funded by Instituto de Salud Carlos III (COV20_00622) and ofounded by European Union (ERDF) “A way of making Europe”; additional funding was received from Amancio Ortega Foundation and Banco de Santander. Authors also receive support from the Generalitat de Catalunya through the CERCA Program