Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity.

BACKGROUND: Recent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries. METHODS: In this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritise drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions. FINDINGS: MR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity in European ancestry. One protein target, SERPINA1 showed a stronger effect in African ancestry but much weaker effect in European ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P = 9.96 × 10-4; OR in Europeans=1.021, 95%CI=0.901 to 1.157, P = 0.745), which suggested that increased level of SERPINA1 will reduce COVID-19 risk in African ancestry. One protein, ICAM1 showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P = 5.94 × 10-4; OR in Africans=1.481, 95%CI=1.008 to 2.176; P = 0.045). The OAS1, SERPINA1 and ICAM1 effects were replicated using updated COVID-19 severity data in the two ancestries respectively, where alternative splicing events in OAS1 and ICAM1 also showed marginal effects on COVID-19 severity in Europeans. The phenome-wide MR of the prioritised targets on 622 complex traits provided information on potential beneficial effects on other diseases and suggested little evidence of adverse effects on major complications. INTERPRETATION: Our study identified six proteins as showing putative causal effects on COVID-19 severity. OAS1 and SERPINA1 were targets of existing drugs in trials as potential COVID-19 treatments. ICAM1, ICAM5 and FCRL3 are related to the immune system. Across the six targets, OAS1 has no reliable instrument in African ancestry; SERPINA1, FCRL3, ICAM5 and ENTPD5 showed a different level of putative causal evidence in European and African ancestries, which highlights the importance of more powerful ancestry-specific GWAS and value of multi-ancestry MR in informing the effects of drug targets on COVID-19 across different populations. This study provides a first step towards clinical investigation of beneficial and adverse effects of COVID-19 drug targets. FUNDING: No.

Reply to Janssen et al. Comment on "Sobczyk, M.K.; Gaunt, T.R. The Effect of Circulating Zinc, Selenium, Copper and Vitamin K1 on COVID-19 Outcomes: A Mendelian Randomization Study. Nutrients 2022, 14, 233".

In their correspondence arising from our recent manuscript [...].

The Effect of Circulating Zinc, Selenium, Copper and Vitamin K1 on COVID-19 Outcomes: A Mendelian Randomization Study.

Background & Aims: Previous results from observational, interventional studies and in vitro experiments suggest that certain micronutrients possess anti-viral and immunomodulatory activities. In particular, it has been hypothesized that zinc, selenium, copper and vitamin K1 have strong potential for prophylaxis and treatment of COVID-19. We aimed to test whether genetically predicted Zn, Se, Cu or vitamin K1 levels have a causal effect on COVID-19 related outcomes, including risk of infection, hospitalization and critical illness. Methods: We employed a two-sample Mendelian Randomization (MR) analysis. Our genetic variants derived from European-ancestry GWAS reflected circulating levels of Zn, Cu, Se in red blood cells as well as Se and vitamin K1 in serum/plasma. For the COVID-19 outcome GWAS, we used infection, hospitalization or critical illness. Our inverse-variance weighted (IVW) MR analysis was complemented by sensitivity analyses including a more liberal selection of variants at a genome-wide sub-significant threshold, MR-Egger and weighted median/mode tests. Results: Circulating micronutrient levels show limited evidence of association with COVID-19 infection, with the odds ratio [OR] ranging from 0.97 (95% CI: 0.87-1.08, p-value = 0.55) for zinc to 1.07 (95% CI: 1.00-1.14, p-value = 0.06)-i.e., no beneficial effect for copper was observed per 1 SD increase in exposure. Similarly minimal evidence was obtained for the hospitalization and critical illness outcomes with OR from 0.98 (95% CI: 0.87-1.09, p-value = 0.66) for vitamin K1 to 1.07 (95% CI: 0.88-1.29, p-value = 0.49) for copper, and from 0.93 (95% CI: 0.72-1.19, p-value = 0.55) for vitamin K1 to 1.21 (95% CI: 0.79-1.86, p-value = 0.39) for zinc, respectively. Conclusions: This study does not provide evidence that supplementation with zinc, selenium, copper or vitamin K1 can prevent SARS-CoV-2 infection, critical illness or hospitalization for COVID-19.

A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance.

Background: The virus SARS-CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19. Methods: To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome-wide genetic colocalisation tests, and polygenic (pan) and cis-Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets. Results: Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble Fas (colocalisation probability >0.9, p=1 × 10-4), implicating Fas-mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis-Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic, and a look-up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19. Conclusions: Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19. Funding: MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Individuals who become infected with the virus that causes COVID-19 can experience a wide variety of symptoms. These can range from no symptoms or minor symptoms to severe illness and death. Key demographic factors, such as age, gender and race, are known to affect how susceptible an individual is to infection. However, molecular factors, such as unique gene mutations and gene expression levels can also have a major impact on patient responses by affecting the levels of proteins in the body. Proteins that are too abundant or too scarce may mean the difference between dying from or surviving COVID-19. Identifying the molecular factors in a host that affect how viruses can infect individuals, evade immune defences or trigger severe illness, could provide new ways to treat patients with COVID-19. Such factors are likely to remain constant, even when the virus mutates into new strains. Hence, insights would likely apply across all virus strains, including current strains, such as alpha and delta, and any new strains that may emerge in the future. Using such a 'natural experiment' approach, Karim et al. compared the genetic profiles of over 30,000 COVID-19 patients and a million healthy individuals. Nine proteins were found to have an impact on COVID-19 infection and disease severity. Four proteins were ranked as top priorities for potential treatment targets. One protein, called CD209 (also known as DC-SIGN), is involved in how the virus enters the host cells, and had one of the strongest associations with COVID-19. Two proteins, called IL-6R and FAS, were involved in the immune response and could be responsible for the immune over-activation often seen in severe COVID-19. Finally, one protein, called OAS1, formed part of the body's innate antiviral defence system and appeared to reduce susceptibility to COVID-19. Knowing more about the proteins that influence the severity of COVID-19 opens up new ways to predict, protect and treat patients who may have severe or fatal reactions to infection. Indeed, one of the identified proteins (IL-6R) had already been targeted in recent clinical trials with some encouraging results. Considering CD209 as a potential receptor for the virus could provide another avenue for therapeutics, similar to previously successful approaches to block the virus' known interaction with a receptor protein. Ultimately, this research could supply an entirely new set of treatment options to help combat the COVID-19 pandemic.