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The major genetic risk factor for severe COVID-19 is inherited from Neanderthals

Abstract

A recent genetic association study1 identified a gene cluster on chromosome 3 as a risk locus for respiratory failure after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A separate study (COVID-19 Host Genetics Initiative)2 comprising 3,199 hospitalized patients with coronavirus disease 2019 (COVID-19) and control individuals showed that this cluster is the major genetic risk factor for severe symptoms after SARS-CoV-2 infection and hospitalization. Here we show that the risk is conferred by a genomic segment of around 50 kilobases in size that is inherited from Neanderthals and is carried by around 50% of people in south Asia and around 16% of people in Europe.

Data availability

The summary statistics of the genome-wide association study that support the finding of this study are available from the COVID-19 Host Genetics Initiative (round 3, ANA_B2_V2: hospitalized patients with COVID-19 compared with population controls; https://www.covid19hg.org/). The genomes used are available from the 1000 Genomes Project (phase 3 release, https://www.internationalgenome.org/) and the Max Planck Institute for Evolutionary Anthropology (Chagyrskaya, Altai and Vindija 33.19, http://cdna.eva.mpg.de/neandertal/). The ancestral alleles are available at Ensembl (release 100, https://www.ensembl.org/). Map data are from OpenStreetMap and available from https://www.openstreetmap.org.

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Acknowledgements

We thank the COVID-19 Host Genetics Initiative for making the data from the genome-wide association study available, and the Max Planck Society and the NOMIS Foundation for funding.

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Authors

Contributions

H.Z. performed the haplotype analysis. H.Z. and S.P. jointly wrote the manuscript.

Corresponding authors

Correspondence to Hugo Zeberg or Svante Pääbo.

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Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature thanks Tobias Lenz, Yang Luo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 Odds ratios for hospitalization due to COVID-19 for cohorts contributing to the meta-analysis (round 3) of the COVID-19 Host Genetics Initiative (rs35044562).

The odds ratio and the P value for the summary effect are odds ratio = 1.60 (95% confidence interval, 1.42–1.79) and P = 3.1 × 10−15 (two-sided z-test, n = 3,199 patients with COVID-19 and 897,488 controls over 8 independent studies). Data are the odds ratios and 95% confidence intervals. HOST(age), UK Biobank European (EUR), GENCOVID, deCODE and BelCovid use European population controls. BRACOVID, Genes & Health and FinnGen use American, south Asian and Finnish population controls, respectively.

Extended Data Fig. 2 Pairwise linkage disequilibrium between diagnostic Neanderthal variants.

Heat map of linkage disequilibrium between genetic variants where one allele is shared with three Neanderthal genomes and missing in 108 Yoruba individuals. The black box highlights a haplotype of 333.8 kb between rs17763537 and rs13068572 (chromosome 3: 45,843,315–46,177,096). Red, r2 correlation; blue, D′ correlation.

Extended Data Fig. 3 Linkage disequilibrium between index variant rs11385942 and the index variant of the COVID-19 Host Genetics Initiative (rs35044562).

Shades of red indicate the extent of linkage disequilibrium (r2) in the populations included in the 1000 Genomes Project. Populations labelled ‘n/a’ are monomorphic for the protective allele of rs35044562. The previously described index variant (rs11385942)1 does not have any genetic variants in linkage disequilibrium (r2 > 0.8) in populations from Africa. Map source data from OpenStreetMap23.

Extended Data Fig. 4 Phylogeny of haplotypes in individuals included in the 1000 Genomes Project and Neanderthals covering the genomic region of the core risk haplotype.

The shaded area highlights a monophyletic group that contains all present-day haplotypes carrying the risk allele at rs35044562 and the haplotypes of the three high-coverage Neanderthals. Arabic numbers show bootstrap support (100 replicates). The tree is rooted with the inferred ancestral human sequence. Scale bar, number of substitutions per nucleotide position.

Extended Data Fig. 5 Frequency differences between south and east Asia for haplotypes introgressed from Neanderthals.

The dashed line indicates the frequency difference for the Neanderthal haplotype that confers risk of severe COVID-19.

Extended Data Table 1 Genetic variants in LD (r2 > 0.98) with rs35044562 and the corresponding Neanderthal variants
Extended Data Table 2 Previous studies that identified gene flow from Neanderthals at the core haplotype

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Zeberg, H., Pääbo, S. The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature (2020). https://doi.org/10.1038/s41586-020-2818-3

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