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 Petrie; Jingyuan 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

doi:10.1101/2021.04.01.21254789

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

Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Research output: Working paper › Preprint › Academic

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.

Original language	English
Number of pages	28
DOIs	https://doi.org/10.1101/2021.04.01.21254789
Publication status	Published - 7-Apr-2021

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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19
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Klaric, L., Gisby, J. S., Papadaki, A., Muckian, M. D., Macdonald-Dunlop, E., Zhao, J. H., Tokolyi, A., Persyn, E., Pairo-Castineira, E., Morris, A. P., Kalnapenkis, A., Richmond, A., Landini, A., Hedman, Å. K., Prins, B., Zanetti, D., Wheeler, E., Kooperberg, C., Yao, C., ... Peters, J. E. (2021). Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19. (medRxiv : the preprint server for health sciences). https://doi.org/10.1101/2021.04.01.21254789

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title = "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.",

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

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Klaric, L, Gisby, JS, Papadaki, A, Muckian, MD, Macdonald-Dunlop, E, Zhao, JH, Tokolyi, A, Persyn, E, Pairo-Castineira, E, Morris, AP, Kalnapenkis, A, Richmond, A, Landini, A, Hedman, ÅK, Prins, B, Zanetti, D, Wheeler, E, Kooperberg, C, Yao, C, Petrie, JR, Fu, J, Folkersen, L, Walker, M, Magnusson, M, Eriksson, N, Mattsson-Carlgren, N, Timmers, PRHJ, Hwang, S-J, Enroth, S, Gustafsson, S, Vosa, U, Chen, Y, Siegbahn, A, Reiner, A, Johansson, Å, Thorand, B, Gigante, B, Hayward, C, Herder, C, Gieger, C, Langenberg, C, Levy, D, Zhernakova, DV, Smith, JG, Campbell, H, Sundstrom, J, Danesh, J, Michaëlsson, K, Suhre, K, Lind, L, Wallentin, L, Padyukov, L, Landén, M, Wareham, NJ, Göteson, A, Hansson, O, Eriksson, P, Strawbridge, RJ, Assimes, TL, Esko, T, Gyllensten, U, Baillie, JK, Paul, DS, Joshi, PK, Butterworth, AS, Mälarstig, A, Pirastu, N, Wilson, JF & Peters, JE 2021 'Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19' medRxiv : the preprint server for health sciences. https://doi.org/10.1101/2021.04.01.21254789

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T1 - Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19

AU - Klaric, Lucija

AU - Gisby, Jack S

AU - Papadaki, Artemis

AU - Muckian, Marisa D

AU - Macdonald-Dunlop, Erin

AU - Zhao, Jing Hua

AU - Tokolyi, Alex

AU - Persyn, Elodie

AU - Pairo-Castineira, Erola

AU - Morris, Andrew P

AU - Kalnapenkis, Anette

AU - Richmond, Anne

AU - Landini, Arianna

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AU - Wheeler, Eleanor

AU - Kooperberg, Charles

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AU - Petrie, John R

AU - Fu, Jingyuan

AU - Folkersen, Lasse

AU - Walker, Mark

AU - Magnusson, Martin

AU - Eriksson, Niclas

AU - Mattsson-Carlgren, Niklas

AU - Timmers, Paul R H J

AU - Hwang, Shih-Jen

AU - Enroth, Stefan

AU - Gustafsson, Stefan

AU - Vosa, Urmo

AU - Chen, Yan

AU - Siegbahn, Agneta

AU - Reiner, Alexander

AU - Johansson, Åsa

AU - Thorand, Barbara

AU - Gigante, Bruna

AU - Hayward, Caroline

AU - Herder, Christian

AU - Gieger, Christian

AU - Langenberg, Claudia

AU - Levy, Daniel

AU - Zhernakova, Daria V

AU - Smith, J Gustav

AU - Campbell, Harry

AU - Sundstrom, Johan

AU - Danesh, John

AU - Michaëlsson, Karl

AU - Suhre, Karsten

AU - Lind, Lars

AU - Wallentin, Lars

AU - Padyukov, Leonid

AU - Landén, Mikael

AU - Wareham, Nicholas J

AU - Göteson, Andreas

AU - Hansson, Oskar

AU - Eriksson, Per

AU - Strawbridge, Rona J

AU - Assimes, Themistocles L

AU - Esko, Tonu

AU - Gyllensten, Ulf

AU - Baillie, J Kenneth

AU - Paul, Dirk S

AU - Joshi, Peter K

AU - Butterworth, Adam S

AU - Mälarstig, Anders

AU - Pirastu, Nicola

AU - Wilson, James F

AU - Peters, James E

PY - 2021/4/7

Y1 - 2021/4/7

N2 - 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.

AB - 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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DO - 10.1101/2021.04.01.21254789

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

ER -

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

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