Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.
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Peer-reviewed
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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.
Description
Acknowledgements: We thank the patients who volunteered to all participating cohorts, and the researchers and clinicians who enrolled them into the respective studies. A full list of acknowledgments can be found in S1 and S2 Tables.
Funder: Lady Davis Institute of the Jewish General Hospital
Funder: Canadian Foundation for Innovation
Funder: NIH Foundation
Funder: Fonds de Recherche Québec Santé (FRQS)
Funder: McGill Interdisciplinary Initiative in Infection and Immunity (MI4)
Funder: Jewish General Hospital Foundation
Funder: Génome Québec; funder-id: http://dx.doi.org/10.13039/100013062
Funder: Public Health Agency of Canada
Funder: McGill University; funder-id: http://dx.doi.org/10.13039/100008582
Funder: Calcul Québec and Compute Canada
Funder: Compute Canada; funder-id: http://dx.doi.org/10.13039/100013020
Funder: Stiftung Universitätsmedizin Essen; funder-id: http://dx.doi.org/10.13039/501100010380
Funder: State of Saarland
Funder: Dr. Rolf M. Schwiete Foundation
Funder: Munich Clinician Scientist Programm
Funder: Netzwerk-Universitaetsmedizin-COVIM; Grant(s): NaFoUniMedCovid19, FKZ: 01KX2021
Funder: Federal Ministry of Education and Research
Funder: Leenaards Foundation
Funder: Santos-Suarez Foundation
Funder: Carigest
Funder: Istituto Buddista Italiano Soka Gakkai; Grant(s): 2020-2016_RIC_3 via project “PAT-COVID: Host genetics and pathogenetic mechanisms of COVID-19”
Funder: e-ASIA Joint Research Program (National Science and Technology Development Agency)
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1553-7404
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Fonds de Recherche Québec Santé (FRQS) (via Genome sequencing of Biobanque Québec COVID-19)
Génome Québec (via support to Genome sequencing of Biobanque Québec COVID-19)
Public Health Agency of Canada (via support to Genome sequencing of Biobanque Québec COVID-19)
Canadian Institutes of Health Research (CIHR) (365825)
Cancer Research UK (C18281/A29019)
Fonds de Recherche Québec Santé (FRQS) (Mérite Clinical Research Scholarship)
Fonds de Recherche Québec Santé (FRQS) (Fellowship)
Canadian Institutes of Health Research (CIHR) (Fellowship)
Vagelos College of Physicians & Surgeons Office for Research (via support to Columbia COVID-19 Biobank)
Biomedical Informatics Resource of the Columbia University Irving Institute for Clinical and Translational Research (CTSA) (via support to Columbia COVID-19 Biobank)
National Center for Advancing Translational Sciences, National Institutes of Health (UL1TR001873, via support to Columbia COVID-19 Biobank)
German Research Foundation (INST 217/1011-1, via support to DeCOI NGS)
NGS Competence Center Tübingen (INST 37/1049-1 Project-ID 286/2020B01 – 428994620)
West German Genome Center (INST 216/981-1 Project Number 407493903)
Technical University of Munich (in-house institutional funding to COMRI cohort)
BONFOR program of the Medical Faculty, University of Bonn (O-149.0134)
Emmy-Noether programm of the German Research Foundation (LU 1944/3-1)
German Research Foundation (SCHU2419/2-1)
German Research Foundation (RY159/3-1)
Swiss National Science Foundation (31CA30_196036, 33IC30_179636 and 314730_192616)
Swiss National Science Foundation (31CA30_196036, 31003A_176097, and 310030_204285)
MIUR project “Dipartimenti di Eccellenza 2018-2020” (via Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020))
Bando Ricerca COVID-19 Toscana (via Azienda Ospedaliero-Universitaria Senese)
charity fund 2020 from Intesa San Paolo (B/2020/0119 for GEN-COVID Multicenter Study (Italy))
Italian Ministry of University and Research (funding for GEN-COVID Multicenter Study (Italy))
Instituto de Salud Carlos III (funding for GEN-COVID (Spain))
GePEM (PI16/01478/Cofinanciado FEDER)
DIAVIR (DTS19/00049/Cofinanciado FEDER)
Resvi-Omics (PI19/01039/Cofinanciado FEDER)
ReSVinext (PI16/01569/Cofinanciado FEDER)
Enterogen (PI19/01090/Cofinanciado FEDER)
Agencia Gallega para la Gestión del Conocimiento en Salud (funding for GEN-COVID (Spain))
BI-BACVIR (PRIS-3)
CovidPhy (SA 304 C)
Agencia Gallega de Innovación (GAIN) (IN607B 2020/08)
GEN-COVID (IN845D 2020/23)
Framework Partnership Agreement between the Consellería de Sanidad de la XUNTA de Galicia (funding for GEN-COVID (Spain))
GENVIP-IDIS (SERGAS-IDIS march 2021 via funding for GEN-COVID (Spain))
consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CB21/06/00103)
F. Hoffmann-La Roche Ltd (funding for COVACTA (Genentech))
U.S. Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, and Biomedical Advanced Research and Development Authority (HHSO100201800036C via funding for COVACTA (Genentech))
Nevada Governor's Office of Economic Development (Healthy Nevada Project via funding to Desert Research Institute (DRI))
Renown Health and the Renown Health Foundation (via funding to Renown Institute for Health Innovation)
Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University (RA(PO) 003/63 and 764002-HE01 for Thai Biobank)
Healthcare-associated Infection Research Group STAR (Special Task Force for Activating Research) (via STF 6100430002-1 for Thai Biobank)
Grant for Development of New Faculty Staff, Ratchadaphiseksomphot Endowment Fund (via DNS 64_002_30_001_2 for Thai Biobank)
e-ASIA Joint Research Program (National Science and Technology Development Agency) (via funding to Thai Biobank)
Health Systems Research Institute, TSRI Fund (CU_FRB640001_01_30_10 via funding to Thai Biobank)
Thailand Research Fund (DPG6180001 via funding to Thai Biobank)
Ratchadapiseksompotch Fund (RA(PO) 003/63)
Ratchadapiseksompotch Fund, Faculty of Medicine,Chulalongkorn University, Bangkok, Thailand (RA(PO) 001/63)
Health Systems Research Institute (64-132)
Ratchadapisek Sompoch Endowment Fund, Chulalongkorn University (764002-HE01)
NHS Blood and Transplant (funding for Interval)
National Institute for Health Research (funding for Interval)
UK Medical Research Council (funding for Interval)
British Heart Foundation (funding for Interval)
Japan Agency for Medical Research and Development (funding for Japan COVID-19 Task Force)
Japan Science and Technology Agency (funding for Interval)
National Center for Global Health and Medicine (Grants-in-Aid for Research (20A2009))
Agency for Medical Research and Development (JP20fk0108416 and JP20fk0108104)
Polish National Science Centre (SZPITALE-JEDNOIMIENNE/2/2020)
Medical Research Agency (2020/ABM /COVID19/0022)
Perelman School of Medicine at University of Pennsylvania (funding for Penn Medicine Biobank)
Smilow family (funding for Penn Medicine Biobank)
National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001878)
Polish Medical Research Agency (2020/ABM/COVID19/0001)
Qatar Foundation for Education, Science and Community Development (funding for Qatar Genome Program and Qatar Biobank)
Saudi Ministry of Health (Saudi COVID-19)
King Abdulaziz City for Science and Technology (Saudi COVID-19)
European Union’s Horizon 2020 research and innovation program (824110 (EASI-Genomics))
Science for Life Laboratory (for Sequencing by the National Genomics Infrastructure SNP&SEQ facility)
Swedish Research Council (for Sequencing by the National Genomics Infrastructure SNP&SEQ facility)
Knut and Alice Wallenberg Foundation (Sequencing by the National Genomics Infrastructure SNP&SEQ facility)
OCRC (funding for UCLA)
Microsoft COVID Compute Funding (funding for UCLA)
Illumina (in-kind donation for UCLA)
UCLA David Geffen School of Medicine - Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Award Program (#20-10)