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      Multi-ancestry fine mapping implicates OAS1 splicing in risk of severe COVID-19

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          Abstract

          The OAS1/2/3 cluster has been identified as a risk locus for severe COVID-19 among individuals of European ancestry, with a protective haplotype of approximately 75 kilobases (kb) derived from Neanderthals in the chromosomal region 12q24.13. This haplotype contains a splice variant of OAS1, which occurs in people of African ancestry independently of gene flow from Neanderthals. Using trans-ancestry fine-mapping approaches in 20,779 hospitalized cases, we demonstrate that this splice variant is likely to be the SNP responsible for the association at this locus, thus strongly implicating OAS1 as an effector gene influencing COVID-19 severity.

          Abstract

          Multi-ancestry fine-mapping of the OAS1/2/3 region shows that a splice site variant in OAS1 is likely responsible for the association of this locus with the risk of severe COVID-19.

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          Most cited references28

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          A global reference for human genetic variation

          The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.
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            Principal components analysis corrects for stratification in genome-wide association studies.

            Population stratification--allele frequency differences between cases and controls due to systematic ancestry differences-can cause spurious associations in disease studies. We describe a method that enables explicit detection and correction of population stratification on a genome-wide scale. Our method uses principal components analysis to explicitly model ancestry differences between cases and controls. The resulting correction is specific to a candidate marker's variation in frequency across ancestral populations, minimizing spurious associations while maximizing power to detect true associations. Our simple, efficient approach can easily be applied to disease studies with hundreds of thousands of markers.
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              Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

              The genetics underlying severe COVID-19 The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science, this issue p. eabd4570, p. eabd4585; see also p. 404
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                Author and article information

                Contributors
                hugo.zeberg@ki.se
                Journal
                Nat Genet
                Nat Genet
                Nature Genetics
                Nature Publishing Group US (New York )
                1061-4036
                1546-1718
                13 January 2022
                13 January 2022
                2022
                : 54
                : 2
                : 125-127
                Affiliations
                [1 ]GRID grid.410370.1, ISNI 0000 0004 4657 1992, Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, ; Boston, MA USA
                [2 ]GRID grid.14709.3b, ISNI 0000 0004 1936 8649, Departments of Medicine, Human Genetics, Epidemiology, Biostatistics and Occupational Health, , McGill University, Lady Davis Institute, Jewish General Hospital, ; Montréal, Québec Canada
                [3 ]GRID grid.21729.3f, ISNI 0000000419368729, Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, , Columbia University, ; New York, NY USA
                [4 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Roslin Institute, , University of Edinburgh, ; Edinburgh, UK
                [5 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, , University of Edinburgh, Western General Hospital, ; Edinburgh, UK
                [6 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Genetics, Perelman School of Medicine, , University of Pennsylvania,, ; Philadelphia, PA USA
                [7 ]GRID grid.239552.a, ISNI 0000 0001 0680 8770, Division of Human Genetics, Department of Pediatrics, , Children’s Hospital of Philadelphia, ; Philadelphia, PA USA
                [8 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, , University of Pennsylvania, ; Philadelphia, PA USA
                [9 ]GRID grid.189504.1, ISNI 0000 0004 1936 7558, Department of Biostatistics, , Boston University School of Public Health, ; Boston, MA USA
                [10 ]GRID grid.14709.3b, ISNI 0000 0004 1936 8649, Department of Human Genetics, , McGill University, ; Montréal, Québec Canada
                [11 ]GRID grid.14709.3b, ISNI 0000 0004 1936 8649, Lady Davis Institute, Jewish General Hospital, , McGill University, ; Montréal, Québec Canada
                [12 ]GRID grid.258799.8, ISNI 0000 0004 0372 2033, Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, , Kyoto University, ; Kyoto, Japan
                [13 ]GRID grid.54432.34, ISNI 0000 0001 0860 6072, Japan Society for the Promotion of Science, ; Tokyo, Japan
                [14 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, , University of Helsinki, ; Helsinki, Finland
                [15 ]GRID grid.38142.3c, ISNI 000000041936754X, Massachusetts General Hospital, Harvard Medical School, ; Boston, MA USA
                [16 ]GRID grid.410355.6, ISNI 0000 0004 0420 350X, Corporal Michael Crescenz VA Medical Center, ; Philadelphia, PA USA
                [17 ]GRID grid.21729.3f, ISNI 0000000419368729, Institute for Genomic Medicine, , Columbia University, ; New York, NY USA
                [18 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Department of Twin Research, King’s College London, ; London, UK
                [19 ]GRID grid.419518.0, ISNI 0000 0001 2159 1813, Max Planck Institute for Evolutionary Anthropology, ; Leipzig, Germany
                [20 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Department of Neuroscience, , Karolinska Institutet, ; Stockholm, Sweden
                Author information
                http://orcid.org/0000-0002-9672-2491
                http://orcid.org/0000-0001-5388-0396
                http://orcid.org/0000-0002-6651-2725
                http://orcid.org/0000-0002-5355-8636
                http://orcid.org/0000-0001-9510-5646
                http://orcid.org/0000-0001-5258-793X
                http://orcid.org/0000-0002-3746-9086
                http://orcid.org/0000-0001-7118-1249
                Article
                996
                10.1038/s41588-021-00996-8
                8837537
                35027740
                ff0fc3c5-ef4d-43ee-818e-51632ba7fb7f
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 14 March 2021
                : 29 November 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/100008738, Jeanssons Stiftelser (Jeansson Foundations);
                Funded by: FundRef https://doi.org/10.13039/501100006285, Magnus Bergvalls Stiftelse (Magnus Bergvall Foundation);
                Funded by: FundRef https://doi.org/10.13039/501100004785, NordForsk;
                Funded by: FundRef https://doi.org/10.13039/501100007202, Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre);
                Award ID: 365825
                Award ID: 409511
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100008240, Fonds de Recherche du Québec-Société et Culture (FRQSC);
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: K25DK128563
                Award ID: UL1TR001873
                Award ID: UL1TR001878
                Award ID: UL1TR001873
                Award Recipient :
                Funded by: Japan Society for the Promotion of Science for Young Scientists
                Funded by: FundRef https://doi.org/10.13039/100006108, U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS);
                Funded by: Smilow family
                Funded by: Canadian Foundation for Innovation Genome Québec The Public Health Agency of Canada The McGill Interdisciplinary Initiative in Infection and Immunity
                Funded by: FundRef https://doi.org/10.13039/501100000268, RCUK | Biotechnology and Biological Sciences Research Council (BBSRC);
                Award ID: BBS/E/D/10002070
                Award ID: BBS/E/D/30002275
                Award ID: BBS/E/D/10002070
                Award ID: BBS/E/D/30002275
                Award Recipient :
                Funded by: Health Data Research UK (references HDR-9004 and HDR-9003)
                Categories
                Brief Communication
                Custom metadata
                © The Author(s), under exclusive licence to Springer Nature America, Inc. 2022

                Genetics
                infectious diseases,genetic association study,immunogenetics
                Genetics
                infectious diseases, genetic association study, immunogenetics

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