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.

Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases

“…This decision was made to fully take advantage of the direct biological link between cis-pQTL and protein level and to prevent highly pleiotropic trans-pQTL influencing our results by breaking the assumptions underlying MR. A systematic assessment of cis vs trans IVs would require the use of all of the most recent MR methods 69,70 and meaningful results would be lost due to multiple testing. Additionally, we performed sensitivity analysis in line with the procedure set out by Zheng et al 43 , for using pQTL as IVs and showed that our causal effect estimates were consistent across multiple MR methods with varying assumptions (Supplementary Figure 8), therefore increasing confidence in the robustness of our results 68 .…”

“…We restricted our MR analysis to cis IVs only, in contrast to previous studies 7,43,68 . This decision was made to fully take advantage of the direct biological link between cis-pQTL and protein level and to prevent highly pleiotropic trans-pQTL influencing our results by breaking the assumptions underlying MR. A systematic assessment of cis vs trans IVs would require the use of all of the most recent MR methods 69,70 and meaningful results would be lost due to multiple testing.…”

Epigenome-wide DNA methylation profiling of healthy COVID-19 recoverees reveals a unique signature in circulating immune cells

“…Higher expression of FAS on CD4+ T cells have been shown to correlate with lower cell counts in Covid-19 patients (28). Along the same lines, elevated circulating levels of the soluble form of FAS have recently been suggested to be causally contributing to the severity of Covid-19, and may in turn originate from genetic splice variants (29). Furthermore, apoptosis of T cells in PBMCs induced by FAS was reported to be increased in Covid-19 patients (30), which along with the involvement of TP53 could explain the lymphopenia frequently observed in COVID-19 subjects.…”

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity

“…From the beginning of the pandemic, MR has played a critical role in providing evidence of modifiable risk factors for COVID-19 2,11,12 . Furthermore, multiple MR studies identified potential therapeutic targets for COVID-19, including OAS1, ABO, IFNAR2, IL-6, ELF5, and FAS [12][13][14][15][16][17][18] . Indeed, some MR findings have been validated by randomized controlled trials, demonstrating the utility of MR [19][20][21][22][23][24] .…”