Stratified analyses refine association between TLR7 rare variants and severe COVID-19
Jannik Boos, Caspar I. van der Made, Gayatri Ramakrishnan, Eamon Coughlan, Rosanna Asselta, Britt-Sabina Löscher, Luca Valenti, Rafael de Cid, Luis Bujanda, Antonio Julià, Erola Pairo-Castineira, J. Kenneth Baillie, Sandra May, Berina Zametica, Julia Heggemann, Agustı́n Albillos, Jesus M. Banales, Jordi Barretina, Natàlia Blay, Paolo Bonfanti, Maria Buti, Javier Fernandez, Sara Marsal, Daniele Prati, Luisa Ronzoni, Nicoletta Sacchi, Valeria Rimoldi, Elvezia Maria Paraboschi, Alessandra Bandera, Flora Peyvandi, Giacomo Grasselli, Francesco Blasi, Francesco Malvestiti, Serena Pelusi, Cristiana Bianco, Lorenzo Miano, Angela Lombardi, Pietro Invernizzi, Alessio Gerussi, Giuseppe Citerio, Andrea Biondi, Maria Grazia Valsecchi, Marina Elena Cazzaniga, Giuseppe Foti, Ilaria Beretta, Mariella D’Angiò, Laura Rachele Bettini, Xavier Farré, Susana Iraola‐Guzmán, Manolis Kogevinas, Gemma Castaño‐Vinyals, Koldo García‐Etxebarria, Beatriz Nafría Jiménez, Mauro D’Amato, Adriana Palom, Colin B. Begg, Sara Clohisey, Charles Hinds, Peter Horby, Julian C. Knight, Lowell Ling, David M. Maslove, Danny McAuley, Johnny Millar, Hugh Montgomery, Alistair Nichol, Peter Openshaw, Alexandre C. Pereira, Chris P. Ponting, Kathy Rowan, Malcolm G. Semple, Manu Shankar‐Hari, Charlotte Summers, Timothy Walsh, J. Kenneth Baillie, Latha Aravindan, Ruth Armstrong, Heather Biggs, Ceilia Boz, Adam Brown, Richard E. Clark, Sara Clohisey, Audrey Coutts, J. Terrence Coyle, Louise Cullum, Sukamal Das, Nicky Day, Lorna Donnelly, Esther Duncan, Angie Fawkes, Paul Fineran, Max Head Fourman, Anita Furlong, James Furniss, Bernadette Gallagher, Tammy Gilchrist, Ailsa Golightly, Fiona Griffiths, Katarzyna Hafezi, Debbie Hamilton
Abstract
Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n 378), compared to 0.24% of controls (odds ratio [OR] 12.3, p 1.27 3 10 10 ). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (OR max 46.5, p 1.74 3 10 15 ). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway.