Butler-Laporte G, Povysil G, Kosmicki JA, Cirulli ET, Drivas T, Furini S, Saad C, Schmidt A, Olszewski P, Korotko U, Quinodoz M, Çelik E, Kundu K, Walter K, Jung J, Stockwell AD, Sloofman LG, Jordan DM, Thompson RC, Del Valle D, Simons N, Cheng E, Sebra R, Schadt EE, Kim-Schulze S, Gnjatic S, Merad M, Buxbaum JD, Beckmann ND, Charney AW, Przychodzen B, Chang T, Pottinger TD, Shang N, Brand F, Fava F, Mari F, Chwialkowska K, Niemira M, Pula S, Baillie JK, Stuckey A, Salas A, Bello X, Pardo-Seco J, Gómez-Carballa A, Rivero-Calle I, Martinón-Torres F, Ganna A, Karczewski KJ, Veerapen K, Bourgey M, Bourque G, Eveleigh RJ, Forgetta V, Morrison D, Langlais D, Lathrop M, Mooser V, Nakanishi T, Frithiof R, Hultström M, Lipcsey M, Marincevic-Zuniga Y, Nordlund J, Schiabor Barrett KM, Lee W, Bolze A, White S, Riffle S, Tanudjaja F, Sandoval E, Neveux I, Dabe S, Casadei N, Motameny S, Alaamery M, Massadeh S, Aljawini N, Almutairi MS, Arabi YM, Alqahtani SA, Al Harthi FS, Almutairi A, Alqubaishi F, Alotaibi S, Binowayn A, Alsolm EA, El Bardisy H, Fawzy M, Cai F, Soranzo N, Butterworth A, Geschwind DH, Arteaga S, Stephens A, Butte MJ, Boutros PC, Yamaguchi TN, Tao S, Eng S, Sanders T, Tung PJ, Broudy ME, Pan Y, Gonzalez A, Chavan N, Johnson R, Pasaniuc B, Yaspan B, Smieszek S, Rivolta C, Bibert S, Bochud PY, Dabrowski M, Zawadzki P, Sypniewski M, Kaja E, Chariyavilaskul P, Nilaratanakul V, Hirankarn N, Shotelersuk V, Pongpanich M, Phokaew C, Chetruengchai W, Tokunaga K, Sugiyama M, Kawai Y, Hasegawa T, Naito T, Namkoong H, Edahiro R, Kimura A, Ogawa S, Kanai T, Fukunaga K, Okada Y, Imoto S, Miyano S, Mangul S, Abedalthagafi MS, Zeberg H, Grzymski JJ, Washington NL, Ossowski S, Ludwig KU, Schulte EC, Riess O, Moniuszko M, Kwasniewski M, Mbarek H, Ismail SI, Verma A, Goldstein DB, Kiryluk K, Renieri A, Ferreira MAR, and Richards JB
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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Biobanque Québécoise de la Covid-19: Brent Richards’s institution has received investigator-initiated grant funding from Eli Lilly, GlaxoSmithKline and Biogen for projects unrelated to this research. He is the CEO of 5 Prime Sciences Inc (www.5primesciences.com). DeCOI: Oliver Witzke has received research grants for clinical studies, speaker’s fees, honoraria and travel expenses from Amgen, Alexion, Astellas, Basilea, Biotest, Bristol-Myers Squibb, Correvio, Chiesi, Gilead, Hexal, Janssen, Dr. F. Köhler Chemie, MSD, Novartis, Roche, Pfizer, Sanofi, Takeda, TEVA and UCB. Kerstin U. Ludwig is co-founder and holds equity in the LAMPseq Diagnostics GmbH. UP serves as ad hoc advisor for Sanofi-Pasteur, BioNtech and Sobi and is member of the SAB of Leukocare. Christoph D. Spinner reports grants, personal fees from AstraZeneca, personal fees and non-financial support from BBraun Melsungen, grants, personal fees and non-financial support from Gilead Sciences, grants and personal fees from Janssen-Cilag, personal fees from Eli Lilly, personal fees from Formycon, personal fees from Roche, other from Apeiron, grants and personal fees from MSD, grants from Cepheid, personal fees from GSK, personal fees from Molecular partners, other from Eli Lilly, personal fees from SOBI during the conduct of the study; personal fees from AbbVie, personal fees from MSD, grants and personal fees from ViiV Healthcare, outside the submitted work. Jochen Schneider received grants and/or personal fees from Gilead Sciences, Janssen-Cilag, and from AbbVie outside the submitted work. Philipp Koehler reports grants or contracts from German Federal Ministry of Research and Education (BMBF) B-FAST (Bundesweites Forschungsnetz Angewandte Surveillance und Testung) and NAPKON (Nationales Pandemie Kohorten Netz, German National Pandemic Cohort Network) of the Network University Medicine (NUM) and the State of North Rhine-Westphalia; Consulting fees Ambu GmbH, Gilead Sciences, Mundipharma Resarch Limited, Noxxon N.V. and Pfizer Pharma; Honoraria for lectures from Akademie für Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, BioRad Laboratories Inc., European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, medupdate GmbH, MedMedia, MSD Sharp & Dohme GmbH, Pfizer Pharma GmbH, Scilink Comunicación Científica SC and University Hospital and LMU Munich; Participation on an Advisory Board from Ambu GmbH, Gilead Sciences, Mundipharma Resarch Limited and Pfizer Pharma; A pending patent currently reviewed at the German Patent and Trade Mark Office; Other non-financial interests from Elsevier, Wiley and Taylor & Francis online outside the submitted work. Oliver A. Cornely reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis; Consulting fees from Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, PSI, Scynexis, Seres; Honoraria for lectures from Abbott, Al-Jazeera Pharmaceuticals, Astellas, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Pfizer; Payment for expert testimony from Cidara; Participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Jannsen, MedPace, Paratek, PSI, Shionogi; A patent at the German Patent and Trade Mark Office (DE 10 2021 113 007.7); Other interests from DGHO, DGI, ECMM, ISHAM, MSG-ERC, Wiley. Genentech: Amy D Stockwell, Fang Cai, and Brian L Yaspan are, or were at the execution of the study, full time employees of Genentech with stock and stock options in Roche. Helix Exome+ and Healthy Nevada Project COVID-19 Phenotypes: Alexandre Bolze, Kelly M Schiabor Barrett, Simon White, Nicole L Washington, Francisco Tanudjaja, Stephen Riffle, Efren Sandoval, and Elizabeth T Cirulli are employees of Helix. Regeneron: Jack A Kosmicki and Manuel AR Ferreira are current employees and/or stockholders of Regeneron Genetics Center or Regeneron Pharmaceuticals. Vanda CALYPSO COVID-19: Bartlomiej Przychodzen and Sandra Smieszek are employees of Vanda Pharmaceuticals Inc.