GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19.
Collaborators (2563)
Millar J ,
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Author information
Affiliations
- 1. Baillie Gifford Pandemic Science Hub, Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.(10 authors)
- Pairo-Castineira E 1, 6, 30
- Rawlik K 1
- Bretherick AD 1, 6
- Zechner M 1, 30
- Griffiths F 1, 30
- Oosthuyzen W 1, 30
- Millar J 1, 10, 30
- Russell CD 1
- Hendry SC 1, 30
- Baillie JK 1, 6, 10, 30
Authors
- 2. School of Life Sciences, Westlake University, Hangzhou, China.(2 authors)
- Qi T 2
- Yang J 2
Authors
- 3. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.(1 author)
- Wu Y 3
Authors
- 4. Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.(4 authors)
- Nassiri I 4
- Malinauskas T 4
- Knight J 4
- Fairfax B 4
Authors
- 5. Faculty of Biological Sciences, University of Leeds, Leeds, UK.(1 author)
- McConkey GA 5
Authors
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ORCIDs linked to this article
- Hinds C | 0000-0001-5094-8324
- Baillie JK | 0000-0001-5258-793X
- Hormis A | 0000-0001-5510-7639
- Nevado J | 0000-0001-5611-2659
- Tucci A | 0000-0001-5644-0070
Nature,
17 May 2023, 617(7962):764-768
https://doi.org/10.1038/s41586-023-06034-3 PMID: 37198478 PMCID: PMC10208981
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This article has been corrected. See
Nature. 2023 Jul;619(7971):E61. doi: 10.1038/s41586-023-06383-z..
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Abstract
Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).
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BioStudies: supplemental material and supporting data
Genes & Proteins (3)
- (1 citation) UniProt - P29597
- (1 citation) UniProt - A6NKX4
- (1 citation) UniProt - P35247
Protein structures in PDBe
-
(1 citation)
PDBe - 4GVJView structure
SNPs (Showing 49 of 49)
- (3 citations) dbSNP - rs117169628
- (2 citations) dbSNP - rs34536443
- (2 citations) dbSNP - rs721917
- (1 citation) dbSNP - rs35482426
- (1 citation) dbSNP - rs41435745
- (1 citation) dbSNP - rs28368148
- (1 citation) dbSNP - rs17713054
- (1 citation) dbSNP - rs1123573
- (1 citation) dbSNP - rs111837807
- (1 citation) dbSNP - rs114301457
- (1 citation) dbSNP - rs879055593
- (1 citation) dbSNP - rs343314
- (1 citation) dbSNP - rs2660
- (1 citation) dbSNP - rs11264349
- (1 citation) dbSNP - rs35463555
- (1 citation) dbSNP - rs11614702
- (1 citation) dbSNP - rs1073165
- (1 citation) dbSNP - rs76608815
- (1 citation) dbSNP - rs77534576
- (1 citation) dbSNP - rs12941811
- (1 citation) dbSNP - rs7528026
- (1 citation) dbSNP - rs8080583
- (1 citation) dbSNP - rs41264915
- (1 citation) dbSNP - rs12610495
- (1 citation) dbSNP - rs188401375
- (1 citation) dbSNP - rs72670002
- (1 citation) dbSNP - rs2478868
- (1 citation) dbSNP - rs60840586
- (1 citation) dbSNP - rs61882275
- (1 citation) dbSNP - rs516246
- (1 citation) dbSNP - rs12046291
- (1 citation) dbSNP - rs142770866
- (1 citation) dbSNP - rs71658797
- (1 citation) dbSNP - rs12585036
- (1 citation) dbSNP - rs7664615
- (1 citation) dbSNP - rs9636867
- (1 citation) dbSNP - rs13276831
- (1 citation) dbSNP - rs915823
- (1 citation) dbSNP - rs11706494
- (1 citation) dbSNP - rs1179620
- (1 citation) dbSNP - rs35705950
- (1 citation) dbSNP - rs8178521
- (1 citation) dbSNP - rs2326788
- (1 citation) dbSNP - rs2271616
- (1 citation) dbSNP - rs2858305
- (1 citation) dbSNP - rs2071590
- (1 citation) dbSNP - rs2897075
- (1 citation) dbSNP - rs2269821
- (1 citation) dbSNP - rs35697037
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Funding
Funders who supported this work.
Biotechnology and Biological Sciences Research Council (4)
Grant ID: BBS/E/D/20002172
Grant ID: BBS/E/D/30002275
Grant ID: BBS/E/RL/230002A
Grant ID: BBS/E/D/10002070
Medical Research Council (10)
Grant ID: HDRUK2021.0125
COVID-19: Data and Connectivity – National Core Study (D&C-NCS)
Professor Andrew Morris, Health Data Research UK
Grant ID: MC_PC_20029
Computational and Disease Genomics
Professor Chris Ponting, University of Edinburgh
Grant ID: MC_UU_00007/15
Structural studies of viruses and their interactions with cells
Professor David Stuart, University of Oxford
Grant ID: MR/V001329/1
ISARIC - Coronavirus Clinical Characterisation Consortium (ISARIC-4C)
Professor John Kenneth Baillie, University of Edinburgh
Grant ID: MC_PC_19025
The genetic basis of invasive meningococcal disease
Dr Vanessa Sancho-Shimizu, Imperial College London
Grant ID: MR/S032304/1
publications
Phase 1 COVID-19 Data and Connectivity – National Core Study (Phase 1 D&C-NCS)
Professor Andrew Morris, Health Data Research UK
Grant ID: MC_PC_20058
publications
Quantitative Traits in Health and Disease
Professor Christopher Haley, University of Edinburgh
Grant ID: MC_UU_00007/10
publications
Determining the causal links and clinical significance of rare genetic variants
Miss Lucija Klaric, University of Edinburgh
Grant ID: MR/R026408/1
publications
COVID-19 GenOMICC-GENOMICS ENGLAND PARTNERSHIP
Professor John Kenneth Baillie, University of Edinburgh
Grant ID: MC_PC_20004
publications
National Institute for Health Research (NIHR) (2)
Grant ID: NF-SI-0513-10150
publications
Grant ID: NIHR201385
publications
Wellcome Trust (1)
Grant ID: 223164/Z/21/Z
publications
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