27 research outputs found
The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males
No full textThe polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor. © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues
No full textVariability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types. © 2021 The Author(s
Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity
No full textThe combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)
Mapping the human genetic architecture of COVID-19
No full textnone3597The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19(1,2), host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases(3-7). They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.noneNiemi, Mari E. K.; Karjalainen, Juha; Liao, Rachel G.; Neale, Benjamin M.; Daly, Mark; Ganna, Andrea; Pathak, Gita A.; Andrews, Shea J.; Kanai, Masahiro; Veerapen, Kumar; Fernandez-Cadenas, Israel; Schulte, Eva C.; Striano, Pasquale; Marttila, Minttu; Minica, Camelia; Marouli, Eirini; Karim, Mohd Anisul; Wendt, Frank R.; Savage, Jeanne; Sloofman, Laura; Butler-Laporte, Guillaume; Kim, Han-Na; Kanoni, Stavroula; Okada, Yukinori; Byun, Jinyoung; Han, Younghun; Uddin, Mohammed Jashim; Smith, George Davey; Willer, Cristen J.; Buxbaum, Joseph D.; Mehtonen, Juha; Finucane, Hilary; Cordioli, Mattia; Martin, Alicia R.; Zhou, Wei; Pasaniuc, Bogdan; Julienne, Hanna; Aschard, Hugues; Shi, Huwenbo; Yengo, Loic; Polimanti, Renato; Ghoussaini, Maya; Schwartzentruber, Jeremy; Dunham, Ian; Chwialkowska, Karolina; Francescatto, Margherita; Trankiem, Amy; Balaconis, Mary K.; Davis, Lea; Lee, Sulggi; Priest, James; Renieri, Alessandra; Sankaran, Vijay G.; van Heel, David; Deelen, Patrick; Richards, J. Brent; Nakanishi, Tomoko; Biesecker, Les; Kerchberger, V. Eric; Baillie, J. Kenneth; Mari, Francesca; Bernasconi, Anna; Baillie, Stefano Ceri; Canakoglu, Arif; Wolford, Brooke; Faucon, Annika; Dutta, Atanu Kumar; Schurmann, Claudia; Harry, Emi; Birney, Ewan; Nguyen, Huy; Nasir, Jamal; Kaunisto, Mari; Solomonson, Matthew; Dueker, Nicole; Vadgama, Nirmal; Limou, Sophie; Rahmouni, Souad; Mbarek, Hamdi; Darwish, Dima; Uddin, Md Mesbah; Albertos, Raquel; Pérez-Tur, Jordi; Li, Ruolin; Folkersen, Lasse; Moltke, Ida; Koelling, Nils; Teumer, Alexander; Kousathanas, Athanasios; Utrilla, Alicia; Verdugo, Ricardo A.; Zárate, Ruth; Medina-Gómez, Carolina; Gómez-Cabrero, David; Carnero-Montoro, Elena; Cadilla, Carmen L.; Moreno-Estrada, Andrés; Garmendia, Adriana; Moya, Leire; Sedaghati-Khayat, Bahar; Boua, Palwendé Romuald; Favé, Marie-Julie; Francioli, Laurent; Lemaçon, Audrey; Migeotte, Isabelle; Patel, Sanjay; Varnai, Reka; Szentpeteri, Jozsef L.; Sipeky, Csilla; Colombo, Francesca; von Hohenstaufen, Kathrin; Lio, Pietro; Vallerga, Costanza; Wang, Qingbo; Tanigawa, Yosuke; Im, Hogune; Han, Chulho; Song, Han; Lim, Jiwoo; Lee, Younhe; Kim, Sugyeong; Im, Sangyoon; Atanasovska, Biljana; Ahmad, Hajar Fauzan; Boer, Cindy; Jansen, Philip; Franke, Lude; Kaja, Elżbieta; Pasko, Dorota; Kennis-Szilagyi, Ingrid; Kornilov, Sergey A.; Prijatelj, Vid; Prokić, Ivana; Sivanadhan, Ilangkumaran; Perumal, Sarala; Esmaeeli, Sahar; Pearson, Nathaniel M.; Auton, Adam; Shelton, Janie F.; Shastri, Anjali J.; Filshtein-Sonmez, Teresa; Coker, Daniella; Symons, Antony; Esparza-Gordillo, Jorge; Aslibekyan, Stella; O’Connell, Jared; Ye, Chelsea; Weldon, Catherine H.; Perera, Minoli; O’Leary, Kevin; Tuck, Matthew; O’Brien, Travis; Meltzer, David; O’Donnell, Peter; Nutescu, Edith; Yang, Guang; Alarcon, Cristina; Herrmann, Stefanie; Mazurek, Sophia; Banagan, Jeff; Hamidi, Zacharia; Barbour, April; Raffat, Noora; Moreno, Diana; Friedman, Paula; Ferwerda, Bart; van de Beek, Diederik; Brouwer, Matthijs C.; Vlaar, Alexander P. J.; Wiersinga, W. Joost; Posthuma, Danielle; Tissink, Elleke; Koos Zwinderman, A. H.; Uffelmann, Emil; van Agtmael, Michiel; Algera, Anne Geke; van Baarle, Frank; Bax, Diane; Beudel, Martijn; Jan Bogaard, Harm; Bomers, Marije; Bonta, Peter I.; Bos, Lieuwe; Botta, Michela; de Brabander, Justin; de Bree, Godelieve; de Bruin, Sanne; Bugiani, Marianna; Bulle, Esther; Chouchane, Osoul; Cloherty, Alex; Dongelmans, Dave; Elbers, Paul; Fleuren, Lucas; Geerlings, Suzanne; Geerts, Bart; Geijtenbeek, Theo; Girbes, Armand; Goorhuis, Bram; Grobusch, Martin P.; Hafkamp, Florianne; Hagens, Laura; Hamann, Jorg; Harris, Vanessa; Hemke, Robert; Hermans, Sabine M.; Heunks, Leo; Hollmann, Markus; Horn, Janneke; Hovius, Joppe W.; de Jong, Menno D.; Koning, Rutger; van Mourik, Niels; Nellen, Jeannine; Nossent, Esther J.; Paulus, Frederique; Peters, Edgar; van der Poll, Tom; Preckel, Bennedikt; Prins, Jan M.; Raasveld, Jorinde; Reijnders, Tom; Schinkel, Michiel; Schultz, Marcus J.; Schuurman, Alex; Sigaloff, Kim; Smit, Marry; Stijnis, Cornelis S.; Stilma, Willemke; Teunissen, Charlotte; Thoral, Patrick; Tsonas, Anissa; van der Valk, Marc; Veelo, Denise; de Vries, Heder; van Vugt, Michèle; Wouters, Dorien; Minnaar, René P.; Kromhout, Adrie; van Uffelen, Kees W. J.; Wolterman, Ruud A.; Roberts, Genevieve; Park, Danny; Ball, Catherine A.; Coignet, Marie; McCurdy, Shannon; Knight, Spencer; Partha, Raghavendran; Rhead, Brooke; Zhang, Miao; Berkowitz, Nathan; Gaddis, Michael; Noto, Keith; Ruiz, Luong; Pavlovic, Milos; Hong, Eurie L.; Rand, Kristin; Girshick, Ahna; Guturu, Harendra; Baltzell, Asher Haug; Rahmouni, Souad; Guntz, Julien; Beguin, Yves; Pigazzini, Sara; Nkambule, Lindokuhle; Bouysran, Youssef; Busson, Adeline; Peyrassol, Xavier; Wilkin, Françoise; Pichon, Bruno; Smits, Guillaume; Vandernoot, Isabelle; Goffard, Jean-Christophe; Georges, Michel; Moutschen, Michel; Misset, Benoit; Darcis, Gilles; Guiot, Julien; Jadot, Laurent; Azarzar, Samira; Dellot, Patricia; Gofflot, Stéphanie; Claassen, Sabine; Bertrand, Axelle; Parzibut, Gilles; Clarinval, Mathilde; Moermans, Catherine; Malaise, Olivier; El Kandoussi, Kamilia; Thonon, Raphaël; Huynen, Pascale; Mesdagh, Alyssia; Melo, Sofia; Jacques, Nicolas; Di Valentin, Emmanuel; Giroule, François; Collignon, Alice; Radermecker, Coraline; Lebrun, Marielle; Perée, Hélène; Latour, Samuel; Barada, Olivia; Sanchez, Judit; Josse, Claire; Boujemla, Bouchra; Meunier, Margot; Mariavelle, Emeline; Anania, Sandy; Gazon, Hélène; Juszczak, Danusia; Fadeur, Marjorie; Camby, Séverine; Meuris, Christelle; Thys, Marie; Jacques, Jessica; Henket, Monique; Léonard, Philippe; Frippiat, Frederic; Giot, Jean-Baptiste; Sauvage, Anne-Sophie; Von Frenckell, Christian; Mni, Myriam; Wéry, Marie; Staderoli, Alicia; Belhaj, Yasmine; Lambermont, Bernard; Morrison, David R.; Mooser, Vincent; Forgetta, Vincenzo; Li, Rui; Ghosh, Biswarup; Laurent, Laetitia; Belisle, Alexandre; Henry, Danielle; Abdullah, Tala; Adeleye, Olumide; Mamlouk, Noor; Kimchi, Nofar; Afrasiabi, Zaman; Rezk, Nardin; Vulesevic, Branka; Bouab, Meriem; Guzman, Charlotte; Petitjean, Louis; Tselios, Chris; Xue, Xiaoqing; Afilalo, Jonathan; Afilalo, Marc; Oliveira, Maureen; Brenner, Bluma; Brassard, Nathalie; Durand, Madeleine; Schurr, Erwin; Lepage, Pierre; Ragoussis, Jiannis; Auld, Daniel; Chassé, Michaël; Kaufmann, Daniel E.; Lathrop, G. Mark; Adra, Darin; Davis, Lea K.; Cox, Nancy J.; Below, Jennifer E.; Sealock, Julia M.; Faucon, Annika B.; Shuey, Megan M.; Polikowsky, Hannah G.; Petty, Lauren E.; Shaw, Douglas M.; Chen, Hung-Hsin; Zhu, Wanying; Ludwig, Kerstin U.; Schröder, Julia; Maj, Carlo; Rolker, Selina; Nöthen, Markus M.; Fazaal, Julia; Keitel, Verena; Jensen, Björn-Erik Ole; Feldt, Torsten; Kurth, Ingo; Marx, Nikolaus; Dreher, Michael; Pink, Isabell; Cornberg, Markus; Illig, Thomas; Lehmann, Clara; Schommers, Philipp; Augustin, Max; Rybniker, Jan; Knopp, Lisa; Eggermann, Thomas; Volland, Sonja; Altmüller, Janine; Berger, Marc M.; Brenner, Thorsten; Hinney, Anke; Witzke, Oliver; Bals, Robert; Herr, Christian; Ludwig, Nicole; Walter, Jörn; Fuchsberger, Christian; Pattaro, Cristian; De Grandi, Alessandro; Pramstaller, Peter; Emmert, David; Melotti, Roberto; Foco, Luisa; Mascalzoni, Deborah; Gögele, Martin; Domingues, Francisco; Hicks, Andrew; Gignoux, Christopher R.; Wicks, Stephen J.; Crooks, Kristy; Barnes, Kathleen C.; Daya, Michelle; Shortt, Jonathan; Rafaels, Nicholas; Chavan, Sameer; Goldstein, David B.; Kiryluk, Krzysztof; Sengupta, Soumitra; Chung, Wendy; Reilly, Muredach P.; Khan, Atlas; Wang, Chen; Povysil, Gundula; Bhardwaj, Nitin; Gharavi, Ali G.; Ionita-Laza, Iuliana; Shang, Ning; O’Byrne, Sheila M.; Nandakumar, Renu; Menon, Amritha; So, Yat S.; Hod, Eldad; Pendrick, Danielle; Kim, Han-Na; Park, Soo-Kyung; Kim, Hyung-Lae; Kang, Chang Kyung; Lee, Hyo-Jung; Song, Kyoung-Ho; Jae Yoon, Kyung; Paik, Nam-Jong; Seok, Woojin; Yoon, Heejun; Joo, Eun-Jeong; Chang, Yoosoo; Ryu, Seungho; Park, Wan Beom; Su Park, Jeong; Un Park, Kyoung; Ham, Sin Young; Jung, Jongtak; Kim, Eu Suk; Kim, Hong Bin; Ellinghaus, David; Degenhardt, Frauke; Cáceres, Mario; Juzenas, Simonas; Lenz, Tobias L.; Albillos, Agustín; Julià, Antonio; Heidecker, Bettina; Garcia, Federico; Kurth, Florian; Tran, Florian; Hanses, Frank; Zoller, Heinz; Holter, Jan C.; Fernández, Javier; Sander, Leif Erik; Rosenstiel, Philip; Koehler, Philipp; de Cid, Rafael; Asselta, Rosanna; Schreiber, Stefan; Hehr, Ute; Prati, Daniele; Baselli, Guido; Valenti, Luca; Bujanda, Luis; Banales, Jesus M.; Duga, Stefano; D’Amato, Mauro; Romero-Gómez, Manuel; Buti, Maria; Invernizzi, Pietro; Franke, Andre; Hov, Johannes R.; Karlsen, Tom H.; Folseraas, Trine; Maya-Miles, Douglas; Teles, Ana; Azuure, Clinton; Wacker, Eike Matthias; Uellendahl-Werth, Florian; ElAbd, Hesham; Arora, Jatin; Lerga-Jaso, Jon; Wienbrandt, Lars; Rühlemann, Malte Christoph; Wendorff, Mareike; Vadla, May Sissel; Lenning, Ole Bernt; Özer, Onur; Myhre, Ronny; Raychaudhuri, Soumya; Tanck, Anja; Gassner, Christoph; Hemmrich-Stanisak, Georg; Kässens, Jan; Figuera Basso, Maria E.; Schulzky, Martin; Wittig, Michael; Braun, Nicole; Wesse, Tanja; Albrecht, Wolfgang; Yi, Xiaoli; Ortiz, Aaron Blandino; Chercoles, Adolfo Garrido; Ruiz, Agustín; Mantovani, Alberto; Holten, Aleksander Rygh; Mayer, Alena; Cherubini, Alessandro; Protti, Alessandro; Aghemo, Alessio; Gerussi, Alessio; Ramirez, Alfredo; Braun, Alice; Barreira, Ana; Lleo, Ana; Kildal, Anders Benjamin; Glück, Andreas; Nolla, Anna Carreras; Latiano, Anna; Dyrhol-Riise, Anne Ma; Muscatello, Antonio; Voza, Antonio; Rando-Segura, Ariadna; Solier, Aurora; Karina, Banasik; Cortes, Beatriz; Mateos, Beatriz; Nafria-Jimenez, Beatriz; Schaefer, Benedikt; Bellinghausen, Carla; Ferrando, Carlos; Quereda, Carmen; Skurk, Carsten; Thibeault, Charlotte; Spinner, Christoph D.; Lange, Christoph; Hu, Cinzia; Cappadona, Claudio; Bianco, Cristiana; Sancho, Cristina; Lihaug Hoff, Dag Arne; Galimberti, Daniela; Jiménez, David; Pestaña, David; Toapanta, David; Azzolini, Elena; Scarpini, Elio; Helbig, Elisa T.; Urrechaga, Eloisa; Paraboschi, Elvezia Maria; Pontali, Emanuele; Reverter, Enric; Navas, Enrique; Arana, Eunate; Sánchez, Félix García; Ceriotti, Ferruccio; Malvestiti, Francesco; Mesonero, Francisco; Pezzoli, Gianni; Lamorte, Giuseppe; Neb, Holger; My, Ilaria; Hernández, Isabel; de Rojas, Itziar; Galván-Femenia, Iván; Heyckendorf, Jan; Rybniker, Jan; Badia, Joan Ramon; Schneider, Jochen; Goikoetxea, Josune; Kraft, Julia; Müller, Karl Erik; Gaede, Karoline I.; Garcia-Etxebarria, Koldo; Tonby, Kristian; Heggelund, Lars; Izquierdo-Sanchez, Laura; Sumoy, Lauro; Lippert, Lena J.; Terranova, Leonardo; Garbarino, Lucia; Téllez, Luis; Roade, Luisa; Ostadreza, Mahnoosh; Intxausti, Maider; Kogevinas, Manolis; Gutiérrez-Stampa, María A.; Vehreschild, Maria J. G. T.; Marquié, Marta; Castoldi, Massimo; Cecconi, Maurizio; Boada, Mercè; Seilmaier, Michael J.; Mazzocco, Michela; Rodríguez-Gandía, Miguel; Ayo, Natale Imaz; Blay, Natalia; Martínez, Nilda; Cornely, Oliver A.; Palmieri, Orazio; Tentorio, Paolo; Rodrigues, Pedro M.; España, Pedro P.; Hoffmann, Per; Bacher, Petra; Suwalski, Phillip; de Pablo, Raúl; Nieto, Rosa; Badalamenti, Salvatore; Ciesek, Sandra; Bombace, Sara; Wilfling, Sibylle; Brunak, Søren; Heilmann-Heimbach, Stefanie; Ripke, Stephan; Bahmer, Thomas; Landmesser, Ulf; Protzer, Ulrike; Rimoldi, Valeria; Skogen, Vegard; Andrade, Victor; Moreno, Victor; Poller, Wolfgang; Farre, Xavier; Wang, Xiaomin; Khodamoradi, Yascha; Karadeniz, Zehra; de Salazar, Adolfo; Palom, Adriana; Garcia-Fernandez, Alba-Estela; Blanco-Grau, Albert; Zanella, Alberto; Bandera, Alessandra; Nebel, Almut; Biondi, Andrea; Caballero-Garralda, Andrea; Gori, Andrea; Lind, Andreas; Fracanzani, Anna Ludovica; Peschuck, Anna; Pesenti, Antonio; de la Horra, Carmen; Milani, Chiara; Paccapelo, Cinzia; Angelini, Claudio; Cea, Cristina; Muñiz-Diaz, Eduardo; Sandoval, Elena; Calderón, Enrique J.; Solligård, Erik; Aziz, Fátima; Martinelli-Boneschi, Filippo; Peyvandi, Flora; Blasi, Francesco; Medrano, Francisco J.; Rodriguez-Frias, Francisco; Müller, Fredrik; Grasselli, Giacomo; Costantino, Giorgio; Cardamone, Giulia; Foti, Giuseppe; Matullo, Giuseppe; Kurihara, Hayato; Afset, Jan Egil; Damås, Jan Kristian; Ampuero, Javier; Martín, Javier; Erdmann, Jeanette; Bergan, Jonas; Goerg, Siegfried; Ferrusquía-Acosta, Jose; Quero, Jose Hernández; Delgado, Juan; Guerrero, Juan M.; Risnes, Kari; Bettini, Laura Rachele; Moreira, Leticia; Gustad, Lise Tuset; Santoro, Luigi; Scudeller, Luigia; Riveiro-Barciela, Mar; Schaefer, Marco; Carrabba, Maria; Valsecchi, Maria G.; Hernandez-Tejero, María; Acosta-Herrera, Marialbert; D’Angiò, Mariella; Baldini, Marina; Cazzaniga, Marina; Ciccarelli, Michele; Bocciolone, Monica; Miozzo, Monica; Chueca, Natalia; Montano, Nicola; Faverio, Paola; Preatoni, Paoletta; Bonfanti, Paolo; Omodei, Paolo; Castro, Pedro; Ferrer, Ricard; Gualtierotti, Roberta; Gallego-Durán, Rocío; Morilla, Rubén; Haider, Sammra; Marsal, Sara; Aneli, Serena; Pelusi, Serena; Bosari, Silvano; Aliberti, Stefano; Dudman, Susanne; Zheng, Tenghao; Pumarola, Tomas; Cejudo, Trinidad Gonzalez; Monzani, Valter; Friaza, Vicente; Peter, Wolfgang; Dopazo, Ximo; Duga, Stefano; May, Sandra; Grimsrud, Marit M.; Gudbjartsson, Daniel F.; Stefansson, Kari; Sulem, Patrick; Sveinbjornsson, Gardar; Melsted, Pall; Norddahl, Gudmundur; Swerford Moore, Kristjan Helgi; Thorsteinsdottir, Unnur; Holm, Hilma; Alarcón-Riquelme, Marta E.; Bernardo, David; Martínez-Bueno, Manuel; Rello, Silvia Rojo; Magi, Reedik; Milani, Lili; Metspalu, Andres; Laisk, Triin; Läll, Kristi; Lepamets, Maarja; Esko, Tõnu; Reimann, Ene; Naaber, Paul; Laane, Edward; Pesukova, Jaana; Peterson, Pärt; Kisand, Kai; Tabri, Jekaterina; Allos, Raili; Hensen, Kati; Starkopf, Joel; Ringmets, Inge; Tamm, Anu; Kallaste, Anne; Alavere, Helene; Metsalu, Kristjan; Puusepp, Mairo; Kristiansson, Kati; Koskelainen, Sami; Perola, Markus; Donner, Kati; Kivinen, Katja; Palotie, Aarno; Palotie, Aarno; Rivolta, Carlo; Bochud, Pierre-Yves; Bibert, Stéphanie; Boillat, Noémie; Nussle, Semira Gonseth; Albrich, Werner; Quinodoz, Mathieu; Kamdar, Dhryata; Suh, Noémie; Neofytos, Dionysios; Erard, Véronique; Voide, Cathy; Bochud, P. Y.; Rivolta, C.; Bibert, S.; Quinodoz, M.; Kamdar, D.; Neofytos, D.; Erard, V.; Voide, C.; Friolet, R.; Vollenweider, P.; Pagani, J. L.; Oddo, M.; zu Bentrup, F. Meyer; Conen, A.; Clerc, O.; Marchetti, O.; Guillet, A.; Guyat-Jacques, C.; Foucras, S.; Rime, M.; Chassot, J.; Jaquet, M.; Viollet, R. Merlet; Lannepoudenx, Y.; Portopena, L.; Desgranges, F.; Filippidis, P.; Guéry, B.; Haefliger, D.; Kampouri, E. E.; Manuel, O.; Munting, A.; Papadimitriou-Olivgeris, M.; Regina, J.; Rochat-Stettler, L.; Suttels, V.; Tadini, E.; Tschopp, J.; Van Singer, M.; Viala, B.; Boillat-Blanco, N.; Brahier, T.; Hügli, O.; Meuwly, J. Y.; Pantet, O.; Nussle, S. Gonseth; Bochud, M.; D’Acremont, V.; Younes, S. Estoppey; Albrich, W. C.; Suh, N.; Cerny, A.; O’Mahony, L.; von Mering, C.; Bochud, P. Y.; Frischknecht, M.; Kleger, G.-R.; Filipovic, M.; Kahlert, C. R.; Wozniak, H.; Negro, T. Rochat; Pugin, J.; Bouras, K.; Knapp, C.; Egger, T.; Perret, A.; Montillier, P.; di Bartolomeo, C.; Barda, B.; de Cid, Rafael; Carreras, Anna; Moreno, Victor; Galván-Femenía, Iván; Blay, Natalia; Farré, Xavier; Sumoy, Lauro; Cortés, Beatriz; Mercader, Josep Maria; Guindo-Martinez, Marta; Torrents, David; Garcia-Aymerich, Judith; Castaño-Vinyals, Gemma; Dobaño, Carlota; Gori, Marco; Renieri, Alessandra; Mondelli, Mario Umberto; Castelli, Francesco; Vaghi, Massimo; Rusconi, Stefano; Montagnani, Francesca; Bargagli, Elena; Franchi, Federico; Mazzei, Maria Antonietta; Cantarini, Luca; Tacconi, Danilo; Feri, Marco; Scala, Raffaele; Spargi, Genni; Nencioni, Cesira; Bandini, Maria; Caldarelli, Gian Piero; Spagnesi, Maurizio; Canaccini, Anna; Ognibene, Agostino; D’Arminio Monforte, Antonella; Girardis, Massimo; Antinori, Andrea; Francisci, Daniela; Schiaroli, Elisabetta; Scotton, Pier Giorgio; Panese, Sandro; Scaggiante, Renzo; Monica, Matteo Della; Capasso, Mario; Fiorentino, Giuseppe; Castori, Marco; Aucella, Filippo; Di Biagio, Antonio; Masucci, Luca; Valente, Serafina; Mandalà, Marco; Zucchi, Patrizia; Giannattasio, Ferdinando; Coviello, Domenico A.; Mussini, Cristina; Bosio, Giancarlo; Tavecchia, Luisa; Crotti, Lia; Rizzi, Marco; La Rovere, Maria Teresa; Sarzi-Braga, Simona; Bussotti, Maurizio; Ravaglia, Sabrina; Artuso, Rosangela; Perrella, Antonio; Romani, Davide; Bergomi, Paola; Catena, Emanuele; Vincenti, Antonella; Ferri, Claudio; Grassi, Davide; Pessina, Gloria; Tumbarello, Mario; Di Pietro, Massimo; Sabrina, Ravaglia; Luchi, Sauro; Barbieri, Chiara; Acquilini, Donatella; Andreucci, Elena; Paciosi, Francesco; Segala, Francesco Vladimiro; Tiseo, Giusy; Falcone, Marco; Lista, Mirjam; Poscente, Monica; De Vivo, Oreste; Petrocelli, Paola; Guarnaccia, Alessandra; Baroni, Silvia; Perticaroli, Valentina; Furini, Simone; Dei, Simona; Benetti, Elisa; Picchiotti, Nicola; Sanarico, Maurizio; Ceri, Stefano; Pinoli, Pietro; Raimondi, Francesco; Biscarini, Filippo; Stella, Alessandra; Bergomi, Mattia; Zguro, Kristina; Capitani, Katia; Tanfoni, Marco; Fallerini, Chiara; Daga, Sergio; Baldassarri, Margherita; Fava, Francesca; Frullanti, Elisa; Valentino, Floriana; Doddato, Gabriella; Giliberti, Annarita; Tita, Rossella; Amitrano, Sara; Bruttini, Mirella; Croci, Susanna; Meloni, Ilaria; Mencarelli, Maria Antonietta; Lo Rizzo, Caterina; Pinto, Anna Maria; Beligni, Giada; Tommasi, Andrea; Di Sarno, Laura; Palmieri, Maria; Carriero, Miriam Lucia; Alaverdian, Diana; Iuso, Nicola; Inchingolo, Gabriele; Busani, Stefano; Bruno, Raffaele; Vecchia, Marco; Belli, Mary Ann; Mantovani, Stefania; Ludovisi, Serena; Quiros-Roldan, Eugenia; Antoni, Melania Degli; Zanella, Isabella; Siano, Matteo; Emiliozzi, Arianna; Fabbiani, Massimiliano; Rossetti, Barbara; Zanelli, Giacomo; Bergantini, Laura; D’Alessandro, Miriana; Cameli, Paolo; Bennet, David; Anedda, Federico; Marcantonio, Simona; Scolletta, Sabino; Guerrini, Susanna; Conticini, Edoardo; Frediani, Bruno; Spertilli, Chiara; Donati, Alice; Guidelli, Luca; Corridi, Marta; Croci, Leonardo; Piacentini, Paolo; Desanctis, Elena; Cappelli, Silvia; Verzuri, Agnese; Anemoli, Valentina; Pancrazi, Alessandro; Lorubbio, Maria; Merlini, Esther; Miraglia, Federica Gaia; Venturelli, Sophie; Cossarizza, Andrea; Vergori, Alessandra; Gabrieli, Arianna; Riva, Agostino; Paciosi, Francesco; Andretta, Francesca; Gatti, Francesca; Parisi, Saverio Giuseppe; Baratti, Stefano; Piscopo, Carmelo; Russo, Roberta; Andolfo, Immacolata; Iolascon, Achille; Carella, Massimo; Merla, Giuseppe; Squeo, Gabriella Maria; Raggi, Pamela; Marciano, Carmen; Perna, Rita; Bassetti, Matteo; Sanguinetti, Maurizio; Giorli, Alessia; Salerni, Lorenzo; Parravicini, Pierpaolo; Menatti, Elisabetta; Trotta, Tullio; Coiro, Gabriella; Lena, Fabio; Martinelli, Enrico; Mancarella, Sandro; Gabbi, Chiara; Maggiolo, Franco; Ripamonti, Diego; Bachetti, Tiziana; Suardi, Claudia; Parati, Gianfranco; Bottà, Giordano; Di Domenico, Paolo; Rancan, Ilaria; Bianchi, Francesco; Colombo, Riccardo; van Heel, David A.; Hunt, Karen A.; Trembath, Richard C.; Huang, Qin Qin; Martin, Hilary C.; Mason, Dan; Trivedi, Bhavi; Wright, John; Finer, Sarah; Griffiths, Christopher J.; Akhtar, Shaheen; Anwar, Mohammad; Arciero, Elena; Ashraf, Samina; Breen, Gerome; Chung, Raymond; Curtis, Charles J.; Chowdhury, Maharun; Colligan, Grainne; Deloukas, Panos; Durham, Ceri; Finer, Sarah; Griffiths, Chris; Huang, Qin Qin; Hurles, Matt; Hunt, Karen A.; Hussain, Shapna; Islam, Kamrul; Khan, Ahsan; Khan, Amara; Lavery, Cath; Lee, Sang Hyuck; Lerner, Robin; MacArthur, Daniel; MacLaughlin, Bev; Martin, Hilary; Mason, Dan; Miah, Shefa; Newman, Bill; Safa, Nishat; Tahmasebi, Farah; Trembath, Richard C.; Trivedi, Bhavi; van Heel, David A.; Wright, John; Smith, Albert V.; Boughton, Andrew P.; Li, Kevin W.; LeFaive, Jonathon; Annis, Aubrey; Jannes, Cinthia E.; Krieger, Jose E.; Pereira, Alexandre C.; Velho, Mariliza; Marques, Emanuelle; Lima, Isabella Ramos; Tada, Mauricio Teruo; Valino, Karina; McCarthy, Mark; Rosenberger, Carrie; Lee, Jon
Host genetics and COVID-19 severity: increasing the accuracy of latest severity scores by Boolean quantum features
No full textThe impact of common and rare variants in COVID-19 host genetics has been widely studied. In particular, in Fallerini et al. (Human genetics, 2022, 141, 147–173), common and rare variants were used to define an interpretable machine learning model for predicting COVID-19 severity. First, variants were converted into sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. After that, the Boolean features, selected by these logistic models, were combined into an Integrated PolyGenic Score (IPGS), which offers a very simple description of the contribution of host genetics in COVID-19 severity.. IPGS leads to an accuracy of 55%–60% on different cohorts, and, after a logistic regression with both IPGS and age as inputs, it leads to an accuracy of 75%. The goal of this paper is to improve the previous results, using not only the most informative Boolean features with respect to the genetic bases of severity but also the information on host organs involved in the disease. In this study, we generalize the IPGS adding a statistical weight for each organ, through the transformation of Boolean features into “Boolean quantum features,” inspired by quantum mechanics. The organ coefficients were set via the application of the genetic algorithm PyGAD, and, after that, we defined two new integrated polygenic scores (IPGSph1 and IPGSph2). By applying a logistic regression with both IPGS, (IPGSph2 (or indifferently IPGSph1) and age as inputs, we reached an accuracy of 84%–86%, thus improving the results previously shown in Fallerini et al. (Human genetics, 2022, 141, 147–173) by a factor of 10%
A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death
No full textAbstract The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10−8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10−8). A total of 113 variants were associated with survival at P-value < 1.0 × 10−5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways
Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study
No full textBackground: Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients.Methods: This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (<60y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene.Results: Overall, we found TLR7 deleterious variants in 2.1% of severely affected males and in none of the asymptomatic participants. The functional gene expression profile analysis demonstrated a reduction in TLR7-related gene expression in patients compared with controls demonstrating an impairment in type I and II IFN responses.Conclusion: Young males with TLR7 loss-of-function variants and severe COVID-19 represent a subset of male patients contributing to disease susceptibility in up to 2% of severe COVID-19. (GEN-COVID Multictr Study
A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death
No full text: The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10-8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10-8). A total of 113 variants were associated with survival at P-value < 1.0 × 10-5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways
Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19
No full textThrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage
Ultra-rare RTEL1 gene variants associate with acute severity of COVID-19 and evolution to pulmonary fibrosis as a specific long COVID disorder
No full textBackground: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel coronavirus that caused an ongoing pandemic of a pathology termed Coronavirus Disease 19 (COVID-19). Several studies reported that both COVID-19 and RTEL1 variants are associated with shorter telomere length, but a direct association between the two is not generally acknowledged. Here we demonstrate that up to 8.6% of severe COVID-19 patients bear RTEL1 ultra-rare variants, and show how this subgroup can be recognized. Methods: A cohort of 2246 SARS-CoV-2-positive subjects, collected within the GEN-COVID Multicenter study, was used in this work. Whole exome sequencing analysis was performed using the NovaSeq6000 System, and machine learning methods were used for candidate gene selection of severity. A nested study, comparing severely affected patients bearing or not variants in the selected gene, was used for the characterisation of specific clinical features connected to variants in both acute and post-acute phases. Results: Our GEN-COVID cohort revealed a total of 151 patients carrying at least one RTEL1 ultra-rare variant, which was selected as a specific acute severity feature. From a clinical point of view, these patients showed higher liver function indices, as well as increased CRP and inflammatory markers, such as IL-6. Moreover, compared to control subjects, they present autoimmune disorders more frequently. Finally, their decreased diffusion lung capacity for carbon monoxide after six months of COVID-19 suggests that RTEL1 variants can contribute to the development of SARS-CoV-2-elicited lung fibrosis. Conclusion: RTEL1 ultra-rare variants can be considered as a predictive marker of COVID-19 severity, as well as a marker of pathological evolution in pulmonary fibrosis in the post-COVID phase. This notion can be used for a rapid screening in hospitalized infected people, for vaccine prioritization, and appropriate follow-up assessment for subjects at risk. Trial Registration NCT04549831 ( www. Clinicaltrial: org )
