Mapping the human genetic architecture of COVID-19

Abstract

The 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-191,2, 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 diseases3,4,5,6,7. 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.

Metadata

Item Type:	Article
Authors/Creators:	Niemi, MEK Karjalainen, J Liao, RG Neale, BM Daly, M Ganna, A Pathak, GA Andrews, SJ Kanai, M Veerapen, K Fernandez-Cadenas, I Schulte, EC Striano, P Marttila, M Minica, C Marouli, E Karim, MA Wendt, FR Savage, J Sloofman, L Butler-Laporte, G Kim, H-N Kanoni, S Okada, Y Byun, J Han, Y Uddin, MJ Smith, GD Willer, CJ Buxbaum, JD Karjalainen, J Mehtonen, J Niemi, MEK Pathak, GA Andrews, SJ Kanai, M Finucane, H Cordioli, M Martin, AR Zhou, W Cordioli, M Pasaniuc, B Julienne, H Aschard, H Shi, H Yengo, L Polimanti, R Ghoussaini, M Schwartzentruber, J Dunham, I Buxbaum, JD Liao, RG Chwialkowska, K Francescatto, M Trankiem, A Balaconis, MK Davis, L Ganna, A Lee, S Priest, J Renieri, A Sankaran, VG van Heel, D Deelen, P Richards, JB Nakanishi, T Biesecker, L Kerchberger, VE Kenneth, J Renieri, A Mari, F Bernasconi, A Ceri, S Canakoglu, A Veerapen, K Wolford, B Trankiem, A Faucon, A Dutta, AK Schurmann, C Harry, E Birney, E Pathak, GA Nguyen, H Nasir, J Priest, J Kaunisto, M Marttila, M Solomonson, M Dueker, N Vadgama, N Andrews, SJ Limou, S Liao, RG Ganna, A Rahmouni, S Mbarek, H Darwish, D Dutta, AK Uddin, MM Fernandez-Cadenas, I Albertos, R Perez-Tur, J Li, R Folkersen, L Moltke, I Koelling, N Schulte, EC Schurmann, C Teumer, A Kousathanas, A Marouli, E Utrilla, A Verdugo, RA Zarate, R Medina-Gomez, C Gomez-Cabrero, D Carnero-Montoro, E Perez-Tur, J Fernandez-Cadenas, I Cadilla, CL Moreno-Estrada, A Garmendia, A Moya, L Sedaghati-Khayat, B Marttila, M Boua, PR Butler-Laporte, G Fave, M-J Francioli, L Lemacon, A Limou, S Migeotte, I Dutta, AK Patel, S Varnai, R Szentpeteri, JL Sipeky, C Colombo, F Francescatto, M von Hohenstaufen, K Lio, P Vallerga, C Striano, P Wang, Q Kanai, M Tanigawa, Y Nakanishi, T Im, H Han, C Song, H Lim, J Lee, Y Kim, S Im, S Atanasovska, B Ahmad, HF Veerapen, K Boer, C Jansen, P Franke, L Chwialkowska, K Kaja, E Pasko, D Kennis-Szilagyi, I Kornilov, SA Prijatelj, V Prokic, I Sivanadhan, I Perumal, S Esmaeeli, S Pearson, NM Zarate, R Karim, MA Nguyen, H Solomonson, M Auton, A Shelton, JF Shastri, AJ Filshtein-Sonmez, T Coker, D Symons, A Esparza-Gordillo, J Aslibekyan, S O'Connell, J Ye, C Weldon, CH Auton, A Perera, M O'Leary, K Tuck, M O'Brien, T Meltzer, D O'Donnell, P Nutescu, E Yang, G Alarcon, C Herrmann, S Mazurek, S Banagan, J Hamidi, Z Barbour, A Raffat, N Moreno, D Friedman, P Ferwerda, B van de Beek, D Brouwer, MC Vlaar, APJ Wiersinga, WJ Posthuma, D Tissink, E Zwinderman, AHK Uffelmann, E van Agtmael, M Algera, AG van Baarle, F Bax, D Beudel, M Bogaard, HJ Bomers, M Bonta, PI Bos, L Botta, M de Brabander, J de Bree, G de Bruin, S Bugiani, M Bulle, E Chouchane, O Cloherty, A Dongelmans, D Elbers, P Fleuren, L Geerlings, S Geerts, B Geijtenbeek, T Girbes, A Goorhuis, B Grobusch, MP Hafkamp, F Hagens, L Hamann, J Harris, V Hemke, R Hermans, SM Heunks, L Hollmann, M Horn, J Hovius, JW de Jong, MD Koning, R van Mourik, N Nellen, J Nossent, EJ Paulus, F Peters, E van der Poll, T Preckel, B Prins, JM Raasveld, J Reijnders, T Schinkel, M Schultz, MJ Schuurman, A Sigaloff, K Smit, M Stijnis, CS Stilma, W Teunissen, C Thoral, P Tsonas, A van der Valk, M Veelo, D de Vries, H van Vugt, M Wouters, D Minnaar, RP Kromhout, A van Uffelen, KWJ Wolterman, RA Roberts, G Park, D Ball, CA Coignet, M McCurdy, S Knight, S Partha, R Rhead, B Zhang, M Berkowitz, N Gaddis, M Noto, K Ruiz, L Pavlovic, M Hong, EL Rand, K Girshick, A Guturu, H Baltzell, AH Niemi, MEK Migeotte, I Rahmouni, S Guntz, J Beguin, Y Cordioli, M Pigazzini, S Nkambule, L Bouysran, Y Busson, A Peyrassol, X Wilkin, F Pichon, B Smits, G Vandernoot, I Goffard, J-C Georges, M Moutschen, M Misset, B Darcis, G Guiot, J Jadot, L Azarzar, S Dellot, P Gofflot, S Claassen, S Bertrand, A Parzibut, G Clarinval, M Moermans, C Malaise, O El Kandoussi, K Thonon, R Huynen, P Mesdagh, A Melo, S Jacques, N Di Valentin, E Giroule, F Collignon, A Radermecker, C Lebrun, M Collignon, A Peree, H Latour, S Barada, O Sanchez, J Josse, C Boujemla, B Meunier, M Mariavelle, E Anania, S Gazon, H Juszczak, D Fadeur, M Camby, S Meuris, C Thys, M Jacques, J Henket, M Leonard, P Frippiat, F Giot, J-B Sauvage, A-S Von Frenckell, C Mni, M Wery, M Staderoli, A Belhaj, Y Lambermont, B Nakanishi, T Morrison, DR Mooser, V Richards, JB Butler-Laporte, G Forgetta, V Li, R Ghosh, B Laurent, L Belisle, A Henry, D Abdullah, T Adeleye, O Mamlouk, N Kimchi, N Afrasiabi, Z Rezk, N Vulesevic, B Bouab, M Guzman, C Petitjean, L Tselios, C Xue, X Afilalo, J Afilalo, M Oliveira, M Brenner, B Brassard, N Durand, M Schurr, E Lepage, P Ragoussis, J Auld, D Chasse, M Kaufmann, DE Lathrop, GM Adra, D Davis, LK Cox, NJ Below, JE Sealock, JM Faucon, AB Shuey, MM Polikowsky, HG Petty, LE Shaw, DM Chen, H-H Zhu, W Ludwig, KU Schroeder, J Maj, C Rolker, S Noethen, MM Fazaal, J Keitel, V Jensen, B-EO Feldt, T Kurth, I Marx, N Dreher, M Pink, I Cornberg, M Illig, T Lehmann, C Schommers, P Augustin, M Rybniker, J Knopp, L Eggermann, T Volland, S Altmueller, J Berger, MM Brenner, T Hinney, A Witzke, O Bals, R Herr, C Ludwig, N Walter, J Fuchsberger, C Pattaro, C De Grandi, A Pramstaller, P Emmert, D Melotti, R Foco, L Mascalzoni, D Gogele, M Domingues, F Hicks, A Gignoux, CR Wicks, SJ Crooks, K Barnes, KC Daya, M Shortt, J Rafaels, N Chavan, S Goldstein, DB Kiryluk, K Sengupta, S Chung, W Reilly, MP Khan, A Wang, C Povysil, G Bhardwaj, N Gharavi, AG Ionita-Laza, I Shang, N O'Byrne, SM Nandakumar, R Menon, A So, YS Hod, E Pendrick, D Kim, H-N Park, S-K Kim, H-L Kang, CK Lee, H-J Song, K-H Yoon, KJ Paik, N-J Seok, W Yoon, H Joo, E-J Chang, Y Ryu, S Park, WB Park, JS Park, KU Ham, SY Jung, J Kim, ES Kim, HB Ellinghaus, D Degenhardt, F Caceres, M Juzenas, S Lenz, TL Albillos, A Julia, A Heidecker, B Schulte, EC Garcia, F Kurth, F Tran, F Hanses, F Zoller, H Holter, JC Fernandez, J Sander, LE Rosenstiel, P Koehler, P de Cid, R Asselta, R Schreiber, S Hehr, U Prati, D Baselli, G Valenti, L Bujanda, L Banales, JM Duga, S D'Amato, M Romero-Gomez, M Buti, M Invernizzi, P Franke, A Hov, JR Karlsen, TH Folseraas, T Maya-Miles, D Teles, A Azuure, C Wacker, EM Uellendahl-Werth, F Elabd, H Arora, J Lerga-Jaso, J Wienbrandt, L Ruehlemann, MC Wendorff, M Vadla, MS Lenning, OB Oezer, O Myhre, R Raychaudhuri, S Tanck, A Gassner, C Hemmrich-Stanisak, G Kaessens, J Basso, MEF Schulzky, M Wittig, M Braun, N Wesse, T Albrecht, W Yi, X Ortiz, AB Garrido Chercoles, A Ruiz, A Mantovani, A Holten, AR Mayer, A Cherubini, A Protti, A Aghemo, A Gerussi, A Ramirez, A Braun, A Barreira, A Lleo, A Kildal, AB Ganna, A Glueck, A Carreras Nolla, A Latiano, A Dyrhol-Riise, AM Muscatello, A Voza, A Rando-Segura, A Solier, A Karina, B Cortes, B Mateos, B Nafria-Jimenez, B Schaefer, B Bellinghausen, C Ferrando, C Quereda, C Skurk, C Thibeault, C Spinner, CD Lange, C Hu, C Cappadona, C Bianco, C Sancho, C Hoff, DAL Galimberti, D Jimenez, D Pestana, D Toapanta, D Azzolini, E Scarpini, E Helbig, ET Urrechaga, E Paraboschi, EM Pontali, E Reverter, E Navas, E Arana, E Garcia Sanchez, F Ceriotti, F Malvestiti, F Mesonero, F Pezzoli, G Lamorte, G Neb, H My, I Hernandez, I de Rojas, I Galvan-Femenia, I Heyckendorf, J Rybniker, J Badia, JR Schneider, J Goikoetxea, J Kraft, J Mueller, KE Gaede, KI Garcia-Etxebarria, K Tonby, K Heggelund, L Izquierdo-Sanchez, L Sumoy, L Lippert, LJ Terranova, L Nkambule, L Garbarino, L Tellez, L Roade, L Ostadreza, M Intxausti, M Kogevinas, M Niemi, MEK Gutierrez-Stampa, MA Vehreschild, MJGT Marquie, M Castoldi, M Cordioli, M Cecconi, M Boada, M Seilmaier, MJ Mazzocco, M Rodriguez-Gandia, M Imaz Ayo, N Blay, N Martinez, N Cornely, OA Palmieri, O Tentorio, P Rodrigues, PM Espana, PP Hoffmann, P Bacher, P Suwalski, P de Pablo, R Nieto, R Badalamenti, S Ciesek, S Bombace, S Pigazzini, S Wilfling, S Brunak, S Heilmann-Heimbach, S Ripke, S Bahmer, T Landmesser, U Protzer, U Rimoldi, V Skogen, V Andrade, V Moreno, V Poller, W Farre, X Wang, X Khodamoradi, Y Karadeniz, Z de Salazar, A Palom, A Garcia-Fernandez, A-E Blanco-Grau, A Zanella, A Bandera, A Nebel, A Biondi, A Caba Llero-Garralda, A Gori, A Lind, A Fracanzani, AL Peschuck, A Pesenti, A De la Horra, C Milani, C Paccapelo, C Angelini, C Cea, C Muniz-Diaz, E Sandoval, E Calderon, EJ Solligard, E Aziz, F Martinelli-Boneschi, F Peyvandi, F Blasi, F Medrano, FJ Rodriguez-Frias, F Mueller, F Grasselli, G Costantino, G Cardamone, G Foti, G Matullo, G Kurihara, H Afset, JE Damas, JK Ampuero, J Martin, J Erdmann, J Bergan, J Goerg, S Ferrusquia-Acosta, J Hernandez Quero, J Delgado, J Guerrero, JM Risnes, K Bettini, LR Moreira, L Gustad, LT Santoro, L Scudeller, L Riveiro-Barciela, M Schaefer, M Carrabba, M Valsecchi, MG Hernandez-Tejero, M Acosta-Herrera, M D'Angio, M Baldini, M Cazzaniga, M Ciccarelli, M Bocciolone, M Miozzo, M Chueca, N Montano, N Faverio, P Preatoni, P Bonfanti, P Omodei, P Castro, P Ferrer, R Gualtierotti, R Gallego-Duran, R Morilla, R Haider, S Marsal, S Aneli, S Pelusi, S Bosari, S Aliberti, S Dudman, S Zheng, T Pumarola, T Gonzalez Cejudo, T Monzani, V Friaza, V Peter, W Dopazo, X Karlsen, TH Duga, S Duga, S May, S Grimsrud, MM Gudbjartsson, DF Stefansson, K Sulem, P Sveinbjornsson, G Melsted, P Norddahl, G Moore, KHS Thorsteinsdottir, U Holm, H Alarcon-Riquelme, ME Bernardo, D Martinez-Bueno, M Rojo Rello, S Magi, R Milani, L Metspalu, A Laisk, T Lall, K Lepamets, M Esko, T Reimann, E Naaber, P Laane, E Pesukova, J Peterson, P Kisand, K Tabri, J Allos, R Hensen, K Starkopf, J Ringmets, I Tamm, A Kallaste, A Alavere, H Metsalu, K Puusepp, M Kristiansson, K Karjalainen, J Koskelainen, S Perola, M Donner, K Kivinen, K Palotie, A Kaunisto, M Palotie, A Rivolta, C Bochud, P-Y Bibert, S Boillat, N Nussle, SG Albrich, W Quinodoz, M Kamdar, D Suh, N Neofytos, D Erard, V Voide, C Bochud, PY Rivolta, C Bibert, S Quinodoz, M Kamdar, D Neofytos, D Erard, V Voide, C Friolet, R Vollenweider, P Pagani, JL Oddo, M zu Bentrup, FM Conen, A Clerc, O Marchetti, O Guillet, A Guyat-Jacques, C Foucras, S Rime, M Chassot, J Jaquet, M Viollet, RM Lannepoudenx, Y Portopena, L Bochud, PY Vollenweider, P Pagani, JL Desgranges, F Filippidis, P Guery, B Haefliger, D Kampouri, EE Manuel, O Munting, A Iou-Olivgeris, MP Regina, J Rochat-Stettler, L Suttels, V Tadini, E Tschopp, J Van Singer, M Viala, B Boillat-Blanco, N Brahier, T Hugli, O Meuwly, JY Pantet, O Nussle, SG Bochud, M D'Acremont, V Younes, SE Albrich, WC Suh, N Cerny, A O'Mahony, L von Mering, C Bochud, PY Frischknecht, M Kleger, G-R Filipovic, M Kahlert, CR Wozniak, H Negro, TR Pugin, J Bouras, K Knapp, C Egger, T Perret, A Montillier, P di Bartolomeo, C Barda, B de Cid, R Carreras, A Moreno, V Kogevinas, M Galvan-Femenia, I Blay, N Farre, X Sumoy, L Cortes, B Mercader, JM Guindo-Martinez, M Torrents, D Garcia-Aymerich, J Castano-Vinyals, G Dobano, C Gori, M Niemi, MEK Renieri, A Mari, F Mondelli, MU Castelli, F Vaghi, M Rusconi, S Montagnani, F Bargagli, E Franchi, F Mazzei, MA Cantarini, L Tacconi, D Feri, M Scala, R Spargi, G Nencioni, C Bandini, M 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Copyright, Publisher and Additional Information:	© 2021 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 23 June 2021 Published (online): 8 July 2021 Published: 16 December 2021
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield)
Depositing User:	Symplectic Sheffield
Date Deposited:	10 Jan 2022 12:02
Last Modified:	10 Jan 2022 12:02
Status:	Published
Publisher:	Springer Nature
Refereed:	Yes
Identification Number:	10.1038/s41586-021-03767-x
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:182256

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Mapping the human genetic architecture of COVID-19

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