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

Jennifer E Huffman; Guillaume Butler-Laporte; Atlas Khan; Erola Pairo-Castineira; Theodore G Drivas; Gina M Peloso; Tomoko Nakanishi; COVID-19 Host Genetics Initiative; Andrea Ganna; Anurag Verma; J Kenneth Baillie; Krzysztof Kiryluk; J Brent Richards; Hugo Zeberg

doi:10.1038/s41588-021-00996-8

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

Nat Genet. 2022 Feb;54(2):125-127. doi: 10.1038/s41588-021-00996-8. Epub 2022 Jan 13.

Authors

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

2',5'-Oligoadenylate Synthetase / genetics*
Black People / genetics
COVID-19 / enzymology
COVID-19 / genetics*
COVID-19 / pathology*
Genetic Predisposition to Disease*
Humans
Linkage Disequilibrium / genetics
Physical Chromosome Mapping*
RNA Splicing / genetics*
Risk Factors
Severity of Illness Index*
White People / genetics

Substances

2',5'-Oligoadenylate Synthetase

Abstract

Publication types

MeSH terms

Substances

Grants and funding