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

Klaric, Lucija (author)
University of Edinburgh
Gisby, Jack S (author)
Imperial College London
Papadaki, Artemis (author)
show more...
Muckian, Marisa D (author)
University of Edinburgh
Macdonald-Dunlop, Erin (author)
Zhao, Jing Hua (author)
University of Cambridge
Tokolyi, Alex (author)
Wellcome Trust Sanger Institute
Persyn, Elodie (author)
Pairo-Castineira, Erola (author)
Morris, Andrew P (author)
University of Manchester
Kalnapenkis, Anette (author)
Karolinska Institutet
Richmond, Anne (author)
Landini, Arianna (author)
Hedman, Åsa K (author)
Karolinska Institutet
Prins, Bram (author)
Zanetti, Daniela (author)
Wheeler, Eleanor (author)
Kooperberg, Charles (author)
Yao, Chen (author)
Karolinska Institutet
Petrie, John R (author)
Fu, Jingyuan (author)
Folkersen, Lasse (author)
Walker, Mark (author)
Magnusson, Martin (author)
Lund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,WCMM- Wallenberg center för molekylär medicinsk forskning,Medicinska fakulteten,Cardiovascular Research - Hypertension,Lund University Research Groups,WCMM-Wallenberg Centre for Molecular Medicine,Faculty of Medicine,North-West University
Eriksson, Niclas, 1978- (author)
Uppsala universitet,Uppsala kliniska forskningscentrum (UCR),Institutionen för medicinska vetenskaper
Mattsson-Carlgren, Niklas (author)
Lund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,Brain Injury After Cardiac Arrest,WCMM- Wallenberg center för molekylär medicinsk forskning,Medicinska fakulteten,Clinical Memory Research,Lund University Research Groups,WCMM-Wallenberg Centre for Molecular Medicine,Faculty of Medicine,Skåne University Hospital
Timmers, Paul R H J (author)
Hwang, Shih-Jen (author)
Enroth, Stefan, 1976- (author)
Uppsala universitet,Institutionen för immunologi, genetik och patologi
Gustafsson, Stefan (author)
Uppsala University,Uppsala universitet,Institutionen för medicinska vetenskaper
Vosa, Urmo (author)
Chen, Yan (author)
Siegbahn, Agneta, 1947- (author)
Uppsala universitet,Institutionen för medicinska vetenskaper
Reiner, Alexander (author)
Johansson, Åsa (author)
Uppsala University,Uppsala universitet,Institutionen för immunologi, genetik och patologi
Thorand, Barbara (author)
Gigante, Bruna (author)
Hayward, Caroline (author)
Herder, Christian (author)
Gieger, Christian (author)
Langenberg, Claudia (author)
Levy, Daniel (author)
Zhernakova, Daria V (author)
Smith, J Gustav (author)
Lund University,Lunds universitet,Kardiologi,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Heart Failure and Mechanical Support,Forskargrupper vid Lunds universitet,Molecular Epidemiology and Cardiology,Cardiovascular Epigenetics,WCMM- Wallenberg center för molekylär medicinsk forskning,Cardiology,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund University Research Groups,WCMM-Wallenberg Centre for Molecular Medicine,Skåne University Hospital
Campbell, Harry (author)
Sundstrom, Johan (author)
Danesh, John (author)
Michaëlsson, Karl, 1959- (author)
Uppsala universitet,Medicinsk epidemiologi
Suhre, Karsten (author)
Lind, Lars (author)
Karolinska Institutet,Uppsala universitet,Institutionen för medicinska vetenskaper
Wallentin, Lars, 1943- (author)
Lund University,Lunds universitet,Uppsala universitet,Uppsala kliniska forskningscentrum (UCR),Institutionen för medicinska vetenskaper,LU Innovation,Sektionen Forskning, samverkan och innovation,Universitetsförvaltningen,Universitetets ledning och förvaltning,Research, Collaboration and Innovation,Central Administration,University Management and Central Administration
Padyukov, Leonid (author)
Landén, Mikael, 1966 (author)
Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Wareham, Nicholas J (author)
Göteson, Andreas, 1991 (author)
Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Hansson, Oskar (author)
Lund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,Clinical Memory Research,Lund University Research Groups,Skåne University Hospital
Eriksson, Per (author)
Karolinska Institutet
Strawbridge, Rona J (author)
Assimes, Themistocles L (author)
Esko, Tonu (author)
Gyllensten, Ulf B. (author)
Uppsala universitet,Institutionen för immunologi, genetik och patologi
Baillie, J Kenneth (author)
Paul, Dirk S (author)
Joshi, Peter K (author)
Butterworth, Adam S (author)
Mälarstig, Anders (author)
Pirastu, Nicola (author)
Wilson, James F (author)
Peters, James E (author)
University of Cambridge
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 (creator_code:org_t)
Cold Spring Harbor Laboratory, 2021
English.
In: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
  • Other publication (other academic/artistic)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Psykiatri (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Psychiatry (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Infektionsmedicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Infectious Medicine (hsv//eng)

Keyword

COVID-19
SARS-CoV-2

Publication and Content Type

vet (subject category)
ovr (subject category)

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By the author/editor
Klaric, Lucija
Gisby, Jack S
Papadaki, Artemi ...
Muckian, Marisa ...
Macdonald-Dunlop ...
Zhao, Jing Hua
show more...
Tokolyi, Alex
Persyn, Elodie
Pairo-Castineira ...
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Richmond, Anne
Landini, Arianna
Hedman, Åsa K
Prins, Bram
Zanetti, Daniela
Wheeler, Eleanor
Kooperberg, Char ...
Yao, Chen
Petrie, John R
Fu, Jingyuan
Folkersen, Lasse
Walker, Mark
Magnusson, Marti ...
Eriksson, Niclas ...
Mattsson-Carlgre ...
Timmers, Paul R ...
Hwang, Shih-Jen
Enroth, Stefan, ...
Gustafsson, Stef ...
Vosa, Urmo
Chen, Yan
Siegbahn, Agneta ...
Reiner, Alexande ...
Johansson, Åsa
Thorand, Barbara
Gigante, Bruna
Hayward, Carolin ...
Herder, Christia ...
Gieger, Christia ...
Langenberg, Clau ...
Levy, Daniel
Zhernakova, Dari ...
Smith, J Gustav
Campbell, Harry
Sundstrom, Johan
Danesh, John
Michaëlsson, Kar ...
Suhre, Karsten
Lind, Lars
Wallentin, Lars, ...
Padyukov, Leonid
Landén, Mikael, ...
Wareham, Nichola ...
Göteson, Andreas ...
Hansson, Oskar
Eriksson, Per
Strawbridge, Ron ...
Assimes, Themist ...
Esko, Tonu
Gyllensten, Ulf ...
Baillie, J Kenne ...
Paul, Dirk S
Joshi, Peter K
Butterworth, Ada ...
Mälarstig, Ander ...
Pirastu, Nicola
Wilson, James F
Peters, James E
show less...
About the subject
MEDICAL AND HEALTH SCIENCES
MEDICAL AND HEAL ...
and Clinical Medicin ...
and Psychiatry
MEDICAL AND HEALTH SCIENCES
MEDICAL AND HEAL ...
and Clinical Medicin ...
MEDICAL AND HEALTH SCIENCES
MEDICAL AND HEAL ...
and Clinical Medicin ...
and Infectious Medic ...
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University of Gothenburg
Uppsala University
Lund University
Karolinska Institutet

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