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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19

Klaric, Lucija ; Gisby, Jack S ; Papadaki, Artemis ; Muckian, Marisa D ; Macdonald-Dunlop, Erin ; Zhao, Jing Hua ; Tokolyi, Alex ; Persyn, Elodie ; Pairo-Castineira, Erola and Morris, Andrew P , et al. (2021)
Abstract

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using... (More)

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.

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organization
publishing date
type
Working paper/Preprint
publication status
published
subject
keywords
COVID-19, SARS-CoV-2
publisher
medRxiv
external identifiers
  • pmid:33851187
DOI
10.1101/2021.04.01.21254789
language
English
LU publication?
yes
id
54f553f2-59e3-4652-bbff-9cae0da8259e
date added to LUP
2021-05-06 08:20:16
date last changed
2022-02-14 16:17:32
@misc{54f553f2-59e3-4652-bbff-9cae0da8259e,
  abstract     = {{<p>Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.</p>}},
  author       = {{Klaric, Lucija and Gisby, Jack S and Papadaki, Artemis and Muckian, Marisa D and Macdonald-Dunlop, Erin and Zhao, Jing Hua and Tokolyi, Alex and Persyn, Elodie and Pairo-Castineira, Erola and Morris, Andrew P and Kalnapenkis, Anette and Richmond, Anne and Landini, Arianna and Hedman, Åsa K and Prins, Bram and Zanetti, Daniela and Wheeler, Eleanor and Kooperberg, Charles and Yao, Chen and Petrie, John R and Fu, Jingyuan and Folkersen, Lasse and Walker, Mark and Magnusson, Martin and Eriksson, Niclas and Mattsson-Carlgren, Niklas and Timmers, Paul R H J and Hwang, Shih-Jen and Enroth, Stefan and Gustafsson, Stefan and Vosa, Urmo and Chen, Yan and Siegbahn, Agneta and Reiner, Alexander and Johansson, Åsa and Thorand, Barbara and Gigante, Bruna and Hayward, Caroline and Herder, Christian and Gieger, Christian and Langenberg, Claudia and Levy, Daniel and Zhernakova, Daria V and Smith, J Gustav and Campbell, Harry and Sundstrom, Johan and Danesh, John and Michaëlsson, Karl and Suhre, Karsten and Lind, Lars and Wallentin, Lars and Padyukov, Leonid and Landén, Mikael and Wareham, Nicholas J and Göteson, Andreas and Hansson, Oskar and Strawbridge, Rona J and Assimes, Themistocles L and Esko, Tonu and Gyllensten, Ulf and Baillie, J Kenneth and Paul, Dirk S and Joshi, Peter K and Butterworth, Adam S and Mälarstig, Anders and Pirastu, Nicola and Wilson, James F and Peters, James E}},
  keywords     = {{COVID-19; SARS-CoV-2}},
  language     = {{eng}},
  month        = {{04}},
  note         = {{Preprint}},
  publisher    = {{medRxiv}},
  title        = {{Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19}},
  url          = {{http://dx.doi.org/10.1101/2021.04.01.21254789}},
  doi          = {{10.1101/2021.04.01.21254789}},
  year         = {{2021}},
}