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: Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
Butler-Laporte, Guillaume;Povysil, Gundula;Kosmicki, Jack A;Cirulli, Elizabeth T;Drivas, Theodore;Furini, Simone;Saad, Chadi;Schmidt, Axel;Olszewski, Pawel;Korotko, Urszula;Quinodoz, Mathieu;Çelik, Elifnaz;Kundu, Kousik;Walter, Klaudia;Jung, Junghyun;Stockwell, Amy D;Sloofman, Laura G;Jordan, Daniel M;Thompson, Ryan C;Del Valle, Diane;Simons, Nicole;Cheng, Esther;Sebra, Robert;Schadt, Eric E;Kim-Schulze, Seunghee;Gnjatic, Sacha;Merad, Miriam;Buxbaum, Joseph D;Beckmann, Noam D;Charney, Alexander W;Przychodzen, Bartlomiej;Chang, Timothy;Pottinger, Tess D;Shang, Ning;Brand, Fabian;Fava, Francesca;Mari, Francesca;Chwialkowska, Karolina;Niemira, Magdalena;Pula, Szymon;Baillie, J Kenneth;Stuckey, Alex;Salas, Antonio;Bello, Xabier;Pardo-Seco, Jacobo;Gómez-Carballa, Alberto;Rivero-Calle, Irene;Martinón-Torres, Federico;Ganna, Andrea;Karczewski, Konrad J;Veerapen, Kumar;Bourgey, Mathieu;Bourque, Guillaume;Eveleigh, Robert Jm;Forgetta, Vincenzo;Morrison, David;Langlais, David;Lathrop, Mark;Mooser, Vincent;Nakanishi, Tomoko;Frithiof, Robert;Hultström, Michael;Lipcsey, Miklos;Marincevic-Zuniga, Yanara;Nordlund, Jessica;Schiabor Barrett, Kelly M;Lee, William;Bolze, Alexandre;White, Simon;Riffle, Stephen;Tanudjaja, Francisco;Sandoval, Efren;Neveux, Iva;Dabe, Shaun;Casadei, Nicolas;Motameny, Susanne;Alaamery, Manal;Massadeh, Salam;Aljawini, Nora;Almutairi, Mansour S;Arabi, Yaseen M;Alqahtani, Saleh A;Al Harthi, Fawz S;Almutairi, Amal;Alqubaishi, Fatima;Alotaibi, Sarah;Binowayn, Albandari;Alsolm, Ebtehal A;El Bardisy, Hadeel;Fawzy, Mohammad;Cai, Fang;Soranzo, Nicole;Butterworth, Adam;Geschwind, Daniel H;Arteaga, Stephanie;Stephens, Alexis;Butte, Manish J;Boutros, Paul C;Yamaguchi, Takafumi N;Tao, Shu;Eng, Stefan;Sanders, Timothy;Tung, Paul J;Broudy, Michael E;Pan, Yu;Gonzalez, Alfredo;Chavan, Nikhil;Johnson, Ruth;Pasaniuc, Bogdan;Yaspan, Brian;Smieszek, Sandra;Rivolta, Carlo;Bibert, Stephanie;Bochud, Pierre-Yves;Dabrowski, Maciej;Zawadzki, Pawel;Sypniewski, Mateusz;Kaja, Elżbieta;Chariyavilaskul, Pajaree;Nilaratanakul, Voraphoj;Hirankarn, Nattiya;Shotelersuk, Vorasuk;Pongpanich, Monnat;Phokaew, Chureerat;Chetruengchai, Wanna;Tokunaga, Katsushi;Sugiyama, Masaya;Kawai, Yosuke;Hasegawa, Takanori;Naito, Tatsuhiko;Namkoong, Ho;Edahiro, Ryuya;Kimura, Akinori;Ogawa, Seishi;Kanai, Takanori;Fukunaga, Koichi;Okada, Yukinori;Imoto, Seiya;Miyano, Satoru;Mangul, Serghei;Abedalthagafi, Malak S;Zeberg, Hugo;Grzymski, Joseph J;Washington, Nicole L;Ossowski, Stephan;Ludwig, Kerstin U;Schulte, Eva C;Riess, Olaf;Moniuszko, Marcin;Kwasniewski, Miroslaw;Mbarek, Hamdi;Ismail, Said I;Verma, Anurag;Goldstein, David B;Kiryluk, Krzysztof;Renieri, Alessandra;Ferreira, Manuel A R;Richards, J Brent
2022
Abstract
: Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/917531
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simulazione ASN
Il report seguente simula gli indicatori relativi alla propria produzione scientifica in relazione alle soglie ASN 2023-2025 del proprio SC/SSD. Si ricorda che il superamento dei valori soglia (almeno 2 su 3) è requisito necessario ma non sufficiente al conseguimento dell'abilitazione. La simulazione si basa sui dati IRIS e sugli indicatori bibliometrici alla data indicata e non tiene conto di eventuali periodi di congedo obbligatorio, che in sede di domanda ASN danno diritto a incrementi percentuali dei valori. La simulazione può differire dall'esito di un’eventuale domanda ASN sia per errori di catalogazione e/o dati mancanti in IRIS, sia per la variabilità dei dati bibliometrici nel tempo. Si consideri che Anvur calcola i valori degli indicatori all'ultima data utile per la presentazione delle domande.
La presente simulazione è stata realizzata sulla base delle specifiche raccolte sul tavolo ER del Focus Group IRIS coordinato dall’Università di Modena e Reggio Emilia e delle regole riportate nel DM 589/2018 e allegata Tabella A. Cineca, l’Università di Modena e Reggio Emilia e il Focus Group IRIS non si assumono alcuna responsabilità in merito all’uso che il diretto interessato o terzi faranno della simulazione. Si specifica inoltre che la simulazione contiene calcoli effettuati con dati e algoritmi di pubblico dominio e deve quindi essere considerata come un mero ausilio al calcolo svolgibile manualmente o con strumenti equivalenti.
