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

doi:10.1038/s41588-021-00996-8

. 2022 Feb;54(2):125-127.

doi: 10.1038/s41588-021-00996-8. Epub 2022 Jan 13.

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

Jennifer E Huffman¹, Guillaume Butler-Laporte², Atlas Khan³, Erola Pairo-Castineira^{4

5}, Theodore G Drivas^{6

7

8}, Gina M Peloso^{1

9}, Tomoko Nakanishi^{10

11

12

13}; COVID-19 Host Genetics Initiative; Andrea Ganna^{14

15}, Anurag Verma^{6

8

16}, J Kenneth Baillie^{4

5}, Krzysztof Kiryluk^{3

17}, J Brent Richards^{2

18}, Hugo Zeberg^{19

20}

Affiliations

¹ Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA, USA.
² Departments of Medicine, Human Genetics, Epidemiology, Biostatistics and Occupational Health, McGill University, Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.
³ Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
⁴ Roslin Institute, University of Edinburgh, Edinburgh, UK.
⁵ Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
⁶ Department of Genetics, Perelman School of Medicine, University of Pennsylvania,, Philadelphia, PA, USA.
⁷ Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸ Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁰ Department of Human Genetics, McGill University, Montréal, Québec, Canada.
¹¹ Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
¹² Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹³ Japan Society for the Promotion of Science, Tokyo, Japan.
¹⁴ Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
¹⁵ Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁶ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
¹⁷ Institute for Genomic Medicine, Columbia University, New York, NY, USA.
¹⁸ Department of Twin Research, King's College London, London, UK.
¹⁹ Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany. hugo.zeberg@ki.se.
²⁰ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. hugo.zeberg@ki.se.

PMID: 35027740
PMCID: PMC8837537
DOI: 10.1038/s41588-021-00996-8

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

Jennifer E Huffman et al. Nat Genet. 2022 Feb.

. 2022 Feb;54(2):125-127.

doi: 10.1038/s41588-021-00996-8. Epub 2022 Jan 13.

Authors

Affiliations

¹ Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA, USA.
² Departments of Medicine, Human Genetics, Epidemiology, Biostatistics and Occupational Health, McGill University, Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.
³ Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.
⁴ Roslin Institute, University of Edinburgh, Edinburgh, UK.
⁵ Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
⁶ Department of Genetics, Perelman School of Medicine, University of Pennsylvania,, Philadelphia, PA, USA.
⁷ Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸ Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁰ Department of Human Genetics, McGill University, Montréal, Québec, Canada.
¹¹ Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
¹² Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹³ Japan Society for the Promotion of Science, Tokyo, Japan.
¹⁴ Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
¹⁵ Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁶ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
¹⁷ Institute for Genomic Medicine, Columbia University, New York, NY, USA.
¹⁸ Department of Twin Research, King's College London, London, UK.
¹⁹ Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany. hugo.zeberg@ki.se.
²⁰ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. hugo.zeberg@ki.se.

PMID: 35027740
PMCID: PMC8837537
DOI: 10.1038/s41588-021-00996-8

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.

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Conflict of interest statement

J.B.R. has served as an advisor to GlaxoSmithKline and Deerfield Capital. His institution has received investigator-initiated grant funding from Eli Lilly, GlaxoSmithKline and Biogen for projects unrelated to this research. He is the founder of 5 Prime Sciences. The other authors declare no competing interests.

Figures

**Fig. 1. LD of the splice acceptor variant in individuals of European and African ancestries.**
a, Plot of LD in individuals of European ancestry (n = 503) shows that 130 variants are in LD (r² > 0.8) with the splice acceptor variant rs10774671 (marked in red). b, Same as in a but for individuals of African ancestry (n = 661). No variants were found to be in LD with the splice acceptor variant. Data are from the 1000 Genomes Project. The x axis shows the hg19 coordinates. Source data

**Fig. 2. Ancestral splice variant and likelihood of hospitalization on SARS-CoV-2 infection.**
a, ORs for COVID-19 hospitalization for carriers of the ancestral splice variant of African ancestry. The plots show the summary effect in individuals of African ancestry (n = 2,787 cases) by meta-analysis of 6 cohorts shown in this study and by the COVID-19 HGI (n = 2,133 cases). Data are presented as ORs ± 95% CIs. b, PIPs using the summary statistics and LD from individuals of European ancestry. c, Same as b but for individuals of African ancestry, using the European PIPs as prior probabilities. d, Same as c but using scaled CADD-scores as prior probabilities for the first (European) step in the fine-mapping analysis. The error bars in a show the 95% CIs. The x axes in b–d show the genomic coordinates in the hg19.

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Update of

Alternative splicing of OAS1 alters the risk for severe COVID-19.
Huffman J, Butler-Laporte G, Khan A, Drivas TG, Peloso GM, Nakanishi T, Verma A, Kiryluk K, Richards JB, Zeberg H. Huffman J, et al. medRxiv [Preprint]. 2021 Mar 25:2021.03.20.21254005. doi: 10.1101/2021.03.20.21254005. medRxiv. 2021. Update in: Nat Genet. 2022 Feb;54(2):125-127. doi: 10.1038/s41588-021-00996-8. PMID: 33791713 Free PMC article. Updated. Preprint.

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References

1. COVID-19 Host Genetics Initiative The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic. Eur. J. Hum. Genet. 2020;28:715–718. doi: 10.1038/s41431-020-0636-6. - DOI - PMC - PubMed
1. Ellinghaus D, et al. Genomewide association study of severe Covid-19 with respiratory failure. N. Engl. J. Med. 2020;383:1522–1534. doi: 10.1056/NEJMoa2020283. - DOI - PMC - PubMed
1. Pairo-Castineira E, et al. Genetic mechanisms of critical illness in COVID-19. Nature. 2021;591:92–98. doi: 10.1038/s41586-020-03065-y. - DOI - PubMed
1. Zhang Q, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370:eabd4570. doi: 10.1126/science.abd4570. - DOI - PMC - PubMed
1. COVID-19 Host Genetics Initiative Mapping the human genetic architecture of COVID-19. Nature10.1038/s41586-021-03767-x (2021). - PMC - PubMed

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[1] COVID-19 Host Genetics Initiative The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic. Eur. J. Hum. Genet. 2020;28:715–718. doi: 10.1038/s41431-020-0636-6. - DOI - PMC - PubMed

[2] COVID-19 Host Genetics Initiative The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic. Eur. J. Hum. Genet. 2020;28:715–718. doi: 10.1038/s41431-020-0636-6. - DOI - PMC - PubMed

[3] Ellinghaus D, et al. Genomewide association study of severe Covid-19 with respiratory failure. N. Engl. J. Med. 2020;383:1522–1534. doi: 10.1056/NEJMoa2020283. - DOI - PMC - PubMed

[4] Ellinghaus D, et al. Genomewide association study of severe Covid-19 with respiratory failure. N. Engl. J. Med. 2020;383:1522–1534. doi: 10.1056/NEJMoa2020283. - DOI - PMC - PubMed

[5] Pairo-Castineira E, et al. Genetic mechanisms of critical illness in COVID-19. Nature. 2021;591:92–98. doi: 10.1038/s41586-020-03065-y. - DOI - PubMed

[6] Pairo-Castineira E, et al. Genetic mechanisms of critical illness in COVID-19. Nature. 2021;591:92–98. doi: 10.1038/s41586-020-03065-y. - DOI - PubMed

[7] Zhang Q, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370:eabd4570. doi: 10.1126/science.abd4570. - DOI - PMC - PubMed

[8] Zhang Q, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370:eabd4570. doi: 10.1126/science.abd4570. - DOI - PMC - PubMed

[9] COVID-19 Host Genetics Initiative Mapping the human genetic architecture of COVID-19. Nature10.1038/s41586-021-03767-x (2021). - PMC - PubMed

[10] COVID-19 Host Genetics Initiative Mapping the human genetic architecture of COVID-19. Nature10.1038/s41586-021-03767-x (2021). - PMC - PubMed

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

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

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