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

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 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.

SUBMITTER: Klaric L

PROVIDER: S-EPMC8043484 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Klaric Lucija L Gisby Jack S JS Papadaki Artemis A Muckian Marisa D MD Macdonald-Dunlop Erin E Zhao Jing Hua JH Tokolyi Alex A Persyn Elodie E Pairo-Castineira Erola E Morris Andrew P AP Kalnapenkis Anette A Richmond Anne A Landini Arianna A Hedman Åsa K ÅK Prins Bram B Zanetti Daniela D Wheeler Eleanor E Kooperberg Charles C Yao Chen C Petrie John R JR Fu Jingyuan J Folkersen Lasse L Walker Mark M Magnusson Martin M Eriksson Niclas N Mattsson-Carlgren Niklas N Timmers Paul R H J PRHJ Hwang Shih-Jen SJ Enroth Stefan S Gustafsson Stefan S Vosa Urmo U Chen Yan Y Siegbahn Agneta A Reiner Alexander A Johansson Åsa Å Thorand Barbara B Gigante Bruna B Hayward Caroline C Herder Christian C Gieger Christian C Langenberg Claudia C Levy Daniel D Zhernakova Daria V DV Smith J Gustav JG Campbell Harry H Sundstrom Johan J Danesh John J Michaëlsson Karl K Suhre Karsten K Lind Lars L Wallentin Lars L Padyukov Leonid L Landén Mikael M Wareham Nicholas J NJ Göteson Andreas A Hansson Oskar O Eriksson Per P Strawbridge Rona J RJ Assimes Themistocles L TL Esko Tonu T Gyllensten Ulf U Baillie J Kenneth JK Paul Dirk S DS Joshi Peter K PK Butterworth Adam S AS Mälarstig Anders A Pirastu Nicola N Wilson James F JF Peters James E JE

medRxiv : the preprint server for health sciences 20210407

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 ...[more]

PMID: 33851187

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Project description:BackgroundEpstein Barr virus (EBV) infects ~ 95% of the population worldwide and is known to cause adverse health outcomes such as Hodgkin's, non-Hodgkin's lymphomas, and multiple sclerosis. There is substantial interest and investment in developing infection-preventing vaccines for EBV. To effectively deploy such vaccines, it is vital that we understand the risk factors for infection. Why particular individuals do not become infected is currently unknown. The current literature, describes complex, often conflicting webs of intersecting factors-sociodemographic, clinical, genetic, environmental-, rendering causality difficult to decipher. We aimed to use Mendelian randomization (MR) to overcome the issues posed by confounding and reverse causality to determine the causal risk factors for the acquisition of EBV.MethodsWe mapped the complex evidence from the literature prior to this study factors associated with EBV serostatus (as a proxy for infection) into a causal diagram to determine putative risk factors for our study. Using data from the UK Biobank of 8422 individuals genomically deemed to be of white British ancestry between the ages of 40 and 69 at recruitment between the years 2006 and 2010, we performed a genome wide association study (GWAS) of EBV serostatus, followed by a Two Sample MR to determine which putative risk factors were causal.ResultsOur GWAS identified two novel loci associated with EBV serostatus. In MR analyses, we confirmed shorter time in education, an increase in number of sexual partners, and a lower age of smoking commencement, to be causal risk factors for EBV serostatus.ConclusionsGiven the current interest and likelihood of a future EBV vaccine, these factors can inform vaccine development and deployment strategies by completing the puzzle of causality. Knowing these risk factors allows identification of those most likely to acquire EBV, giving insight into what age to vaccinate and who to prioritise when a vaccine is introduced.

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

Publications

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

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