Abstract
Courses of SARS-CoV-2 infections are highly variable, ranging from asymptomatic to lethal COVID-19. Though research has shown that host genetic factors contribute to this variability, cohort-based joint analyses of variants from the entire allelic spectrum in individuals with confirmed SARS-CoV-2 infections are still lacking. Here, we present the results of whole genome sequencing in 1,220 mainly vaccine-naïve individuals with confirmed SARS-CoV-2 infection, including 827 hospitalized COVID-19 cases. We observed the presence of autosomal-recessive or likely compound heterozygous monogenic disorders in six individuals, all of which were hospitalized and significantly younger than the rest of the cohort. We did not observe any suggestive causal variants in or around the established risk gene TLR7. Burden testing in the largest population subgroup (i.e., Europeans) suggested nominal enrichments of rare variants in coding and non-coding regions of interferon immune response genes in the overall analysis and male subgroup. Case-control analyses of more common variants confirmed associations with previously reported risk loci, with the key locus at 3p21 reaching genome-wide significance. Polygenic scores accurately captured risk in an age-dependent manner. By enabling joint analyses of different types of variation across the entire frequency spectrum, this data will continue to contribute to the elucidation of COVID-19 etiology.
Copyright: © 2024 Schmidt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
MeSH terms
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Adult
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Aged
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COVID-19* / genetics
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COVID-19* / virology
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Case-Control Studies
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Female
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Genetic Predisposition to Disease
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Genome-Wide Association Study
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Humans
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Male
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Middle Aged
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SARS-CoV-2* / genetics
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Toll-Like Receptor 7 / genetics
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Whole Genome Sequencing* / methods
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Young Adult
Substances
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Toll-Like Receptor 7
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TLR7 protein, human
Grants and funding
Genome sequencing was supported by institutional grants from the German Research Foundation (Deutsche Forschungsgemeinschaft - DFG) (286/2020B01 - 428994620), and was performed by the DFG-funded NGS Competence Center Tübingen (NCCT; INST 37/1049-1) and West German Genome Center (WGGC; INST 216/981-1). The study was supported in part by an unrestricted grant from Illumina, Berlin. The following investigators were financially supported: ASchm (BONFOR program of the Medical Faculty of the University of Bonn (O-149.0134); RA (DFG (428902522)), SKH (Emmy Noether Programme of the DFG (KI 2091/2-1), other DFG grants (459153572), SFB/TRR237-B29 (369799452), ERC Starting Grant (101076303)), AH (Stiftung Universitätsmedizin Essen); ECS (DFG (Schu 2914/2-1). ECS was further supported by the Munich Clinician Scientist Program (MCSP). JLS, MMN, and KUL are members of the DFG-funded Cluster of Excellence ImmunoSensation - EXC2151 – 390873048. PK reports grants or contracts from German Federal Ministry of Research and Education (BMBF), B-FAST (Bundesweites Forschungsnetz Angewandte Surveillance und Testung) and German National Pandemic Cohort Network (Nationales Pandemie Kohorten Netz - NAPKON) of the Network University Medicine (Netzwerk-Universitätsmedizin - NUM) and the State of North Rhine-Westphalia. Recruitment of participating cohorts was funded by institutional support of: the Technical University of Munich (COMRI cohort), the Institute of Human Genetics, University Hospital Bonn (BoSCO cohort), the Federal Ministry of Education and Research (NUM - COVIM: 01KX2021, ReCOV cohort), the Rolf M. Schweite Stiftung and the State of Saarland (2020-013; both CORSAAR cohort), the Uniklinik RWTH Aachen and the Institute for Human Genetics and Genomic Medicine at the University Hospital Aachen (COVAS cohort), the UME and the Stiftung Universitätsmedizin Essen (COVES cohort), Hessisches Ministerium für Wissenschaft und Kunst (CCHROMO cohort), the Healthcare System of the Autonomous Province of Bolzano/Bozen (Val Gardena cohort), the University Hospital Düsseldorf (COVID-19 UKD Biobank study), the Ministry of Science and Culture (MWK) of Lower-Saxony (COVID-19 MWK Biobank study), the Free State of Bavaria under the Excellence Strategy of the Federal State Government (LMUExcellent, CORKUM cohort), the Care-for-Rare Foundation (Ped-COVID-19 cohort), the BMBF (01KI20343; COVIMMUNE cohort), and the Bavarian State Ministry for Science and Art (COVUR cohort). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.