Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19
作者： James F Wilson , James F Wilson , Dirk S Paul , Dirk S Paul , Shih-Jen Hwang
DOI: 10.1101/2021.04.01.21254789
关键词: Biology 、 Locus (genetics) 、 Cytokine receptor 、 Mediator 、 Immunology 、 Quantitative trait locus 、 Apoptosis 、 Exon 、 Alternative splicing 、 Receptor
摘要: 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 mediate COVID-19. Using protein quantitative trait loci (pQTL) data the SCALLOP consortium, involving meta-analysis up 26,494 individuals, genome-wide association Host Genetics Initiative, MR for 157 severity biomarkers. We significant results five proteins: FAS, TNFRSF10A, CCL2, EPHB4 LGALS9. Further evaluation these candidates using sensitivity analyses colocalization testing provided strong evidence implicate apoptosis-associated cytokine receptor FAS as a causal mediator This effect was specific disease. RNA-seq 4,778 demonstrate pQTL at locus genetically influenced alternate splicing causing skipping exon 6. show risk allele very increases proportion transcripts lacking 6, thereby soluble FAS. Soluble acts decoy FAS-ligand, inhibiting apoptosis induced through membrane-bound In summary, novel genetic mechanism contributes highlighting pathway may be promising therapeutic target.
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