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

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

Research output: Working paperPreprintAcademic


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.

Original languageEnglish
Number of pages28
Publication statusPublished - 7-Apr-2021

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