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

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Klaric, LucijaUniversity of Edinburgh (author)

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

BookEnglish2021

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Cold Spring Harbor Laboratory,2021

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LIBRIS-ID:oai:gup.ub.gu.se/304288
https://gup.ub.gu.se/publication/304288URI
https://doi.org/10.1101/2021.04.01.21254789DOI
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-460708URI
https://lup.lub.lu.se/record/54f553f2-59e3-4652-bbff-9cae0da8259eURI
http://kipublications.ki.se/Default.aspx?queryparsed=id:233851187URI

Supplementary language notes

Language:English

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SwePubSwePub

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Subject category:vet swepub-contenttype
Subject category:ovr swepub-publicationtype

Notes

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 and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Psykiatri hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Psychiatry hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Infektionsmedicin hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Infectious Medicine hsv//eng
COVID-19
SARS-CoV-2

Added entries (persons, corporate bodies, meetings, titles ...)

Gisby, Jack SImperial College London (author)
Papadaki, Artemis (author)
Muckian, Marisa DUniversity of Edinburgh (author)
Macdonald-Dunlop, Erin (author)
Zhao, Jing HuaUniversity of Cambridge (author)
Tokolyi, AlexWellcome Trust Sanger Institute (author)
Persyn, Elodie (author)
Pairo-Castineira, Erola (author)
Morris, Andrew PUniversity of Manchester (author)
Kalnapenkis, AnetteKarolinska Institutet (author)
Richmond, Anne (author)
Landini, Arianna (author)
Hedman, Åsa KKarolinska Institutet (author)
Prins, Bram (author)
Zanetti, Daniela (author)
Wheeler, Eleanor (author)
Kooperberg, Charles (author)
Yao, ChenKarolinska Institutet (author)
Petrie, John R (author)
Fu, Jingyuan (author)
Folkersen, Lasse (author)
Walker, Mark (author)
Magnusson, MartinKarolinska Institutet,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(Swepub:lu)medf-mma (author)
Eriksson, Niclas,1978-Uppsala universitet,Uppsala kliniska forskningscentrum (UCR),Institutionen för medicinska vetenskaper(Swepub:uu)nieri103 (author)
Mattsson-Carlgren, NiklasLund 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(Swepub:lu)med-nmn (author)
Timmers, Paul R H J (author)
Hwang, Shih-Jen (author)
Enroth, Stefan,1976-Uppsala universitet,Institutionen för immunologi, genetik och patologi(Swepub:uu)stenr451 (author)
Gustafsson, StefanUppsala University,Uppsala universitet,Institutionen för medicinska vetenskaper(Swepub:uu)stegu732 (author)
Vosa, Urmo (author)
Chen, Yan (author)
Siegbahn, Agneta,1947-Uppsala universitet,Institutionen för medicinska vetenskaper(Swepub:uu)agsie424 (author)
Reiner, Alexander (author)
Johansson, ÅsaUppsala University,Uppsala universitet,Institutionen för immunologi, genetik och patologi(Swepub:uu)asjoh108 (author)
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 GustavLund 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(Swepub:lu)med-gvs (author)
Campbell, Harry (author)
Sundstrom, Johan (author)
Danesh, John (author)
Michaëlsson, Karl,1959-Uppsala universitet,Medicinsk epidemiologi(Swepub:uu)karlmich (author)
Suhre, Karsten (author)
Lind, LarsKarolinska Institutet,Uppsala universitet,Institutionen för medicinska vetenskaper(Swepub:uu)larslind (author)
Wallentin, Lars,1943-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(Swepub:lu)luin-lrw (author)
Padyukov, Leonid (author)
Landén, Mikael,1966Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xlandt (author)
Wareham, Nicholas J (author)
Göteson, Andreas,1991Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xgotea (author)
Hansson, OskarLund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,Clinical Memory Research,Lund University Research Groups,Skåne University Hospital(Swepub:lu)mphy-ohn (author)
Eriksson, PerKarolinska Institutet (author)
Strawbridge, Rona J (author)
Assimes, Themistocles L (author)
Esko, Tonu (author)
Gyllensten, Ulf B.Uppsala universitet,Institutionen för immunologi, genetik och patologi(Swepub:uu)ulfgyll (author)
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 EUniversity of Cambridge (author)
University of EdinburghImperial College London (creator_code:org_t)

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In:medRxiv : the preprint server for health sciences: Cold Spring Harbor Laboratory, s. 1-28

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