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. 2022 Nov 3;18(11):e1010367.
doi: 10.1371/journal.pgen.1010367. eCollection 2022 Nov.

Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

Guillaume Butler-Laporte  1   2 , Gundula Povysil  3 , Jack A Kosmicki  4 , Elizabeth T Cirulli  5 , Theodore Drivas  6   7   8 , Simone Furini  9 , Chadi Saad  10 , Axel Schmidt  11 , Pawel Olszewski  12 , Urszula Korotko  12   13 , Mathieu Quinodoz  14   15   16 , Elifnaz Çelik  14   16 , Kousik Kundu  17   18 , Klaudia Walter  18 , Junghyun Jung  19   20 , Amy D Stockwell  21 , Laura G Sloofman  22 , Daniel M Jordan  23 , Ryan C Thompson  24 , Diane Del Valle  25 , Nicole Simons  25 , Esther Cheng  25 , Robert Sebra  26 , Eric E Schadt  26 , Seunghee Kim-Schulze  27 , Sacha Gnjatic  25 , Miriam Merad  28 , Joseph D Buxbaum  22 , Noam D Beckmann  28 , Alexander W Charney  29 , Bartlomiej Przychodzen  30 , Timothy Chang  31 , Tess D Pottinger  3 , Ning Shang  32 , Fabian Brand  33 , Francesca Fava  9   34   35 , Francesca Mari  9   34   35 , Karolina Chwialkowska  12   13 , Magdalena Niemira  36 , Szymon Pula  12 , J Kenneth Baillie  37   38   39   40 , Alex Stuckey  41 , Antonio Salas  42   43   44 , Xabier Bello  42   43   44 , Jacobo Pardo-Seco  42   43   44 , Alberto Gómez-Carballa  42   43   44 , Irene Rivero-Calle  43   44   45 , Federico Martinón-Torres  43   44   45 , Andrea Ganna  46   47 , Konrad J Karczewski  48   49 , Kumar Veerapen  48   49 , Mathieu Bourgey  50   51 , Guillaume Bourque  50   51   52 , Robert Jm Eveleigh  50   51 , Vincenzo Forgetta  2 , David Morrison  2 , David Langlais  51   52 , Mark Lathrop  51   52 , Vincent Mooser  52 , Tomoko Nakanishi  2   52   53   54 , Robert Frithiof  55 , Michael Hultström  1   2   55   56 , Miklos Lipcsey  55   57 , Yanara Marincevic-Zuniga  58 , Jessica Nordlund  58 , Kelly M Schiabor Barrett  5 , William Lee  5 , Alexandre Bolze  5 , Simon White  5 , Stephen Riffle  5 , Francisco Tanudjaja  5 , Efren Sandoval  5 , Iva Neveux  59 , Shaun Dabe  60 , Nicolas Casadei  61   62 , Susanne Motameny  63   64 , Manal Alaamery  65   66 , Salam Massadeh  65   66 , Nora Aljawini  65   66 , Mansour S Almutairi  65   66 , Yaseen M Arabi  67 , Saleh A Alqahtani  68   69 , Fawz S Al Harthi  70 , Amal Almutairi  70 , Fatima Alqubaishi  70 , Sarah Alotaibi  70 , Albandari Binowayn  70 , Ebtehal A Alsolm  70 , Hadeel El Bardisy  70 , Mohammad Fawzy  70 , Fang Cai  21 , Nicole Soranzo  18 , Adam Butterworth  18 ; COVID-19 Host Genetics Initiative; DeCOI Host Genetics Group; GEN-COVID Multicenter Study (Italy); Mount Sinai Clinical Intelligence Center; GEN-COVID consortium (Spain); GenOMICC Consortium; Japan COVID-19 Task Force; Regeneron Genetics Center; Daniel H Geschwind  31 , Stephanie Arteaga  31 , Alexis Stephens  71 , Manish J Butte  71   72 , Paul C Boutros  73 , Takafumi N Yamaguchi  73 , Shu Tao  73 , Stefan Eng  73 , Timothy Sanders  74 , Paul J Tung  74 , Michael E Broudy  74 , Yu Pan  74 , Alfredo Gonzalez  73 , Nikhil Chavan  74 , Ruth Johnson  75 , Bogdan Pasaniuc  73   76   77 , Brian Yaspan  21 , Sandra Smieszek  30 , Carlo Rivolta  14   15   16 , Stephanie Bibert  78 , Pierre-Yves Bochud  78 , Maciej Dabrowski  79 , Pawel Zawadzki  79   80 , Mateusz Sypniewski  79 , Elżbieta Kaja  79   81 , Pajaree Chariyavilaskul  82 , Voraphoj Nilaratanakul  83 , Nattiya Hirankarn  84 , Vorasuk Shotelersuk  85 , Monnat Pongpanich  86 , Chureerat Phokaew  87 , Wanna Chetruengchai  88 , Katsushi Tokunaga  89 , Masaya Sugiyama  89 , Yosuke Kawai  90 , Takanori Hasegawa  91 , Tatsuhiko Naito  92   93 , Ho Namkoong  94 , Ryuya Edahiro  92   95 , Akinori Kimura  96 , Seishi Ogawa  97   98   99 , Takanori Kanai  100 , Koichi Fukunaga  101 , Yukinori Okada  92   93   102   103   104 , Seiya Imoto  105 , Satoru Miyano  91 , Serghei Mangul  19 , Malak S Abedalthagafi  70 , Hugo Zeberg  106 , Joseph J Grzymski  59 , Nicole L Washington  5 , Stephan Ossowski  61   62 , Kerstin U Ludwig  11   107 , Eva C Schulte  108   109   110 , Olaf Riess  61   62 , Marcin Moniuszko  111   112 , Miroslaw Kwasniewski  12   13 , Hamdi Mbarek  10 , Said I Ismail  10 , Anurag Verma  7   8   113 , David B Goldstein  3   114 , Krzysztof Kiryluk  3   32 , Alessandra Renieri  9   34   35 , Manuel A R Ferreira  4 , J Brent Richards  1   2   52   115   116   117
Affiliations

Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

Guillaume Butler-Laporte et al. PLoS Genet. .

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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Conflict of interest statement

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.

Figures

Fig 1
Fig 1. Maps of countries contributing data to the consortium.
Sample sizes (cases and controls) for each phenotype were added and represented on the logarithmic scale by each circle. Relative contribution to each phenotype is represented by the three colors. Maps obtained from https://www.naturalearthdata.com/.
Fig 2
Fig 2. Participant’s genome projection on the first and second genetic principal components of the 1000G reference panel.
AFR: African ancestry. AMR: admixed American ancestry. EAS: east Asian ancestry. EUR: European ancestry. MID: middle eastern ancestry. SAS: south Asian ancestry.
Fig 3
Fig 3. Single variant exome-wide association study Manhattan plot (MAF>0.1%).
QQ-plot available in the S1 Fig. Black dashed line demarcates the genome-wide significance threshold (p < 5x10-8).
Fig 4
Fig 4. Exome burden test ACAT p-value meta-analysis Manhattan plots and QQ plots.
QQ-plot available in the S6 Fig. Black dashed line demarcates the Bonferroni significance threshold (p < 0.5/20,000).
Fig 5
Fig 5. Sex-stratified TLR7 analyses.
See this image and copyright information in PMC

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