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.
FörderungenBavarian State Ministry for Science and Art BMBF Care-for-Rare Foundation Free State of Bavaria under the Excellence Strategy of the Federal State Government (LMUExcellent) Ministry of Science and Culture (MWK) of Lower-Saxony University Hospital Dusseldorf Healthcare System of the Autonomous Province of Bolzano/Bozen Hessisches Ministerium fur Wissenschaft und Kunst UME Institute for Human Genetics and Genomic Medicine at the University Hospital Aachen Uniklinik RWTH Aachen State of Saarland Rolf M. Schweite Stiftung Federal Ministry of Education and Research Institute of Human Genetics, University Hospital Bonn Technical University of Munich State of North Rhine-Westphalia German National Pandemic Cohort Network (Nationales Pandemie Kohorten Netz NAPKON) of the Network University Medicine (Netzwerk-Universitatsmedizin -NUM) B-FAST (Bundesweites Forschungsnetz Angewandte Surveillance und Testung) German Federal Ministry of Research and Education (BMBF) Munich Clinician Scientist Program (MCSP) Stiftung Universitatsmedizin Essen ERC Starting Grant DFG BONFOR program of the Medical Faculty of the University of Bonn Illumina, Berlin German Research Foundation (Deutsche Forschungsgemeinschaft DFG)